Personalised intrinsic network topography mapping and functional connectivity deficits in Autism Spectrum Disorder Biol. Psychiatry (IF 11.412) Pub Date : 2018-03-17 Erin W. Dickie, Stephanie H. Ameis, Saba Shahab, Navona Calarco, Dawn E. Smith, Dayton Miranda, Joseph D. Viviano, Aristotle N. Voineskos
Background Recent advances demonstrate individually specific variation in brain architecture in healthy individuals using fMRI data. To our knowledge, the effects of individually specific variation in complex brain disorders have not been previously reported. Methods We developed a novel approach (Personalized Intrinsic Network topography, PINT) for localizing individually specific resting state networks using conventional resting state fMRI scans. Using cross-sectional data from participants with Autism Spectrum Disorder (ASD; n=393) and Typically Developing controls (TD; n=496) across 15 sites we tested: 1) effect of diagnosis and age on the variability of intrinsic network locations and 2) whether prior findings of functional connectivity differences in ASD as compared to TD remain after PINT application. Results We found greater variability in the spatial locations of resting state networks within individuals with ASD as compared to TD. In TD participants, variability decreased from childhood into adulthood, and increased again in late-life, following a ‘U-shaped’ pattern, which was not present in those with ASD. Comparison of intrinsic connectivity between groups revealed that the application of PINT decreased the number of hypo-connected regions in ASD. Conclusions Our results provide a new framework for measuring altered brain functioning in neurodevelopmental disorders that may have implications for tracking developmental course, phenotypic heterogeneity, and ultimately treatment response. We underscore the importance of accounting for individual variation in the study of complex brain disorders.
Title: A comprehensive analysis of nuclear-encoded mitochondrial genes in schizophrenia Biol. Psychiatry (IF 11.412) Pub Date : 2018-03-15 Vanessa F. Gonçalves, Carolina Cappi, Christian M. Hagen, Adolfo Sequeira, Marquis P. Vawter, Andriy Derkach, Clement C. Zai, Paula L. Hedley, Jonas Bybjerg-Grauholm, Jennie G. Pouget, Ari B. Cuperfain, Patrick F. Sullivan, Michael Christiansen, James L. Kennedy, Lei Sun
Background The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest mitochondrial dysfunction may play a role in SCZ, but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ. Methods We conducted gene-based and gene-set analyses using summary association results from the Schizophrenia Psychiatric Genomics Consortium GWAS (PGC-SCZ2) comprising 35,476 cases and 46,839 controls. We applied the MAGMA method to three sets of nuclear-encoded mitochondrial genes: oxidative phosphorylation genes, other nuclear-encoded mitochondrial genes, and genes involved in nucleus-mitochondria crosstalk. Furthermore, we conducted a replication study using the iPSYCH SCZ sample of 2,290 cases and 21,621 controls. Results In the PGC-SCZ2 sample, 1,186 mitochondrial genes were analyzed among which 159 had p-values <0.05 and 19 remained significant after multiple testing correction. A meta-analysis of 818 genes combining the PGC-SCZ2 and iPSYCH samples resulted in 104 nominally significant and nine significant genes, suggesting a polygenic model for the nuclear-encoded mitochondrial genes. Gene-set analysis, however, did not show significant results. In an in silico protein-protein interaction (PPI) network analysis, 14 mitochondrial genes interacted directly with 158 SCZ risk genes identified in PGC-SCZ2 (permutation p=0.02), and aldosterone signaling in epithelial cells and mitochondrial dysfunction pathways appeared to be over-represented in this network of mitochondrial and SCZ risk genes. Conclusion This study provides evidence that specific aspects of mitochondrial function may play a role in SCZ, but we did not observe its broad involvement even using a large sample.
Clinical presentation of a complex neurodevelopmental disorder caused by mutations in ADNP Biol. Psychiatry (IF 11.412) Pub Date : 2018-03-15 Anke Van Dijck, Anneke T. Vulto-van Silfhout, Elisa Cappuyns, Ilse M. van der Werf, Grazia M. Mancini, Andreas Tzschach, Raphael Bernier, Illana Gozes, Evan E. Eichler, Corrado Romano, Anna Lindstrand, Ann Nordgren, Malin Kvarnung, Tjitske Kleefstra, Bert B.A. de Vries, Sébastien Küry, Jill A. Rosenfeld, Marije E. Meuwissen, Geert Vandeweyer, R Frank Kooy
Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported amongst the most frequent. ADNP mutations have been identified in children with autism spectrum disorder co-morbid with intellectual disability, facial features and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable genotype-phenotype correlations. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature and hormonal deficiencies are common co-morbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features, distinctive from other autism/ID syndromes. In addition, our data show preliminary evidence of a genotype-phenotype correlation.
Metabotropic glutamate receptor 5 as a target for the treatment of depression and smoking: robust preclinical data but inconclusive clinical efficacy Biol. Psychiatry (IF 11.412) Pub Date : 2018-03-09 Samuel A. Barnes, Douglas J. Sheffler, Svetlana Semenova, Nicholas D.P. Cosford, Anton Bespalov
The ability of novel pharmacological compounds to improve outcomes in preclinical models is often not translated into clinical efficacy. Psychiatric disorders do not have biological boundaries and identifying mechanisms to improve the translational bottleneck between preclinical and clinical research domains is an important and challenging task. Glutamate transmission is disrupted in several neuropsychiatric disorders. Metabotropic glutamate (mGlu) receptors represent a diverse class of receptors that contribute to excitatory neurotransmission. Given the wide, yet region-specific manner of expression, developing pharmacological compounds to modulate mGlu receptor activity provides an opportunity to subtly and selectively modulate excitatory neurotransmission. This review focuses on the potential involvement of mGlu5 receptor disruption in major depressive disorders (MDD) and substance use disorders (SUD). We have provided an overview of the justification of targeting mGlu5 receptors in the treatment of these disorders, summarized the preclinical evidence for negatively modulating mGlu5 receptors as a therapeutic target for MDD and nicotine dependence and highlighted the outcomes of recent clinical trials. While the evidence of mGlu5 negative allosteric modulation has been promising in preclinical investigations, these beneficial effects have not translated into clinical efficacy. In this review, we have identified key challenges that may contribute to poor clinical translation and provided suggested approaches moving forward to potentially improve the translation from preclinical to clinical domains. Such approaches may increase the success of clinical trials, and may reduce the translational bottleneck that exists in drug discovery for psychiatric disorders.
Dopaminergic Disturbances in Tourette Syndrome: An Integrative Account Biol. Psychiatry (IF 11.412) Pub Date : 2018-03-09 Tiago V. Maia, Vasco A. Conceição
Tourette syndrome (TS) is thought to involve dopaminergic disturbances, but the nature of those disturbances remains controversial. Existing hypotheses suggest that TS involves (1) supersensitive dopamine receptors, (2) overactive dopamine transporters that cause low tonic but high phasic dopamine, (3) presynaptic dysfunction in dopamine neurons, or (4) dopaminergic hyperinnervation. We review evidence that contradicts the first two hypotheses; we also note that the last two hypotheses have traditionally been considered too narrowly, as explaining only small subsets of findings. We review all studies that have used positron emission tomography and single-photon emission computerized tomography to investigate the dopaminergic system in TS. The seemingly diverse findings from those studies have typically been interpreted as pointing to distinct mechanisms, as evidenced by the various hypotheses concerning the nature of dopaminergic disturbances in TS. We show, however, that the hyperinnervation hypothesis provides a simple, parsimonious explanation for all such seemingly diverse findings. Dopaminergic hyperinnervation likely causes increased tonic and phasic dopamine. We have previously shown, using a computational model of the role of dopamine in the basal ganglia, that increased tonic and phasic dopamine likely increase the propensities to express and to learn tics, respectively. There is therefore a plausible mechanistic link between dopaminergic hyperinnervation and TS, via increased tonic and phasic dopamine. To further bolster this argument, we review evidence showing that all medications that are effective for TS reduce signaling by tonic dopamine, phasic dopamine, or both.
PET studies of the glial cell marker TSPO in psychosis patients - a meta-analysis using individual participant data Biol. Psychiatry (IF 11.412) Pub Date : 2018-03-06 Pontus Plavén-Sigray, Granville J. Matheson, Karin Collste, Abhishekh H. Ashok, Jennifer M. Coughlin, Oliver D. Howes, Romina Mizrahi, Martin G. Pomper, Pablo Rusjan, Mattia Veronese, Yuchuan Wang, Simon Cervenka
BackgroundAccumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography (PET) and radioligands binding to the translocator protein (TSPO), which is expressed in glial cells in brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined if patients with first episode psychosis and schizophrenia had altered TSPO levels compared to healthy control subjects.MethodsPubMed was searched for studies comparing patients with psychosis to healthy controls using second-generation TSPO radioligands. The outcome measure was distribution volume (VT), an index of TSPO levels, in frontal cortex (FC), temporal cortex (TC) and hippocampus (HIP). Bayes factors (BF) were applied to examine the relative support for higher, lower or no difference in patients’ TSPO levels compared to healthy controls.ResultsFive studies, with 75 participants with first-episode psychosis or schizophrenia and 77 healthy controls were included. BF showed strong support for lower VT in patients relative to no difference (all BF>32), or relative to higher VT (all BF>422), in all brain regions. From the posterior distributions, mean patient-control differences in standardized VT values were -0.48 for FC (95% credible interval (CredInt)=-0.88 to -0.09), -0.47 for TC (CredInt=-0.87 to -0.07) and -0.63 for HIP (CredInt=-1.00 to -0.25).ConclusionThe lower levels of TSPO observed in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.
High Throughput Phenotyping for Dimensional Psychopathology in Electronic Health Records Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-26 Thomas H. McCoy Jr., Sheng Yu, Kamber L. Hart, Victor M. Castro, Hannah E. Brown, James N. Rosenquist, Alysa E. Doyle, Pieter J. Vuijk, Tianxi Cai, Roy H. Perlis
Background Relying on diagnostic categories of neuropsychiatric illness obscures the complexity of these disorders. Capturing multiple dimensional measures of neuropathology could facilitate the clinical and neurobiological investigation of cognitive and behavioral phenotypes. Methods We developed a natural language processing–based approach to extract five symptom dimensions, based on the National Institute of Mental Health Research Domain Criteria definitions, from narrative clinical notes. Estimates of Research Domain Criteria loading were derived from a cohort of 3619 individuals with 4623 hospital admissions. We applied this tool to a large corpus of psychiatric inpatient admission and discharge notes (2010–2015), and using the same cohort we examined face validity, predictive validity, and convergent validity with gold standard annotations. Results In mixed-effect models adjusted for sociodemographic and clinical features, greater negative and positive symptom domains were associated with a shorter length of stay (β = −.88, p = .001 and β = −1.22, p < .001, respectively), while greater social and arousal domain scores were associated with a longer length of stay (β = .93, p < .001 and β = .81, p = .007, respectively). In fully adjusted Cox regression models, a greater positive domain score at discharge was also associated with a significant increase in readmission risk (hazard ratio = 1.22, p < .001). Positive and negative valence domains were correlated with expert annotation (by analysis of variance [df = 3], R2 = .13 and .19, respectively). Likewise, in a subset of patients, neurocognitive testing was correlated with cognitive performance scores (p < .008 for three of six measures). Conclusions This shows that natural language processing can be used to efficiently and transparently score clinical notes in terms of cognitive and psychopathologic domains.
Genome-wide Association Study of Dimensional Psychopathology Using Electronic Health Records Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-26 Thomas H. McCoy Jr., Victor M. Castro, Kamber L. Hart, Amelia M. Pellegrini, Sheng Yu, Tianxi Cai, Roy H. Perlis
Background Genetic studies of neuropsychiatric disease strongly suggest an overlap in liability. There are growing efforts to characterize these diseases dimensionally rather than categorically, but the extent to which such dimensional models correspond to biology is unknown. Methods We applied a newly developed natural language processing method to extract five symptom dimensions based on the National Institute of Mental Health Research Domain Criteria definitions from narrative hospital discharge notes in a large biobank. We conducted a genome-wide association study to examine whether common variants were associated with each of these dimensions as quantitative traits. Results Among 4687 individuals, loci in three of five domains exceeded a genome-wide threshold for statistical significance. These included a locus spanning the neocortical development genes RFPL3 and RFPL3S for arousal (p = 2.29 × 10−8) and one spanning the FPR3 gene for cognition (p = 3.22 × 10−8). Conclusions Natural language processing identifies dimensional phenotypes that may facilitate the discovery of common genetic variation that is relevant to psychopathology.
Translational Assessments of Reward and Anhedonia Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-24 Andre Der-Avakian, Diego A. Pizzagalli
Loss of pleasure (clinically referred to as anhedonia), impairments in other reward-related processes such as reward learning, motivation, and reward valuation, and blunted affect characterize several mood and other psychiatric disorders. Despite the availability of many therapeutic options for these disorders, reward-related impairments remain challenging to treat and often persist despite alleviation of other symptoms. Lack of animal models of reward-related impairments and affect that have high construct and predictive validity is a key obstacle to developing novel treatments. This review will highlight: 1) guidelines to consider when developing translatable animal models; and 2) recent efforts to develop new reward-related assessments in humans and non-human animals that have been translated or back-translated from one species to another. The procedures described in this review are used to assess aspects of reward learning, motivated behavior, reward valuation, and affect. In several cases, researchers have attempted to implement task parameters that are as identical as possible to the parallel parameters used in existing cross-species tasks, with the goal of improving the translation of preclinical drug discovery findings to the clinic. In this regard, Dr. Athina Markou had great influence on conceptualizing the development and use of translational animal models of reward-related processes. Thus, this review is dedicated to Dr. Markou and her tireless efforts throughout her career to understand and treat reward-related impairments across several psychiatric disorders.
Ventral CA3 Activation Mediates Prophylactic Ketamine Efficacy Against Stress-Induced Depressive-Like Behavior Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-23 Alessia Mastrodonato, Randy Martinez, Ina P. Pavlova, Christina T. LaGamma, Rebecca A. Brachman, Alfred J. Robison, Christine A. Denny
Background We previously reported that a single injection of ketamine prior to stress protects against the onset of depressive-like behavior and attenuates learned fear. However, the molecular pathways and brain circuits underlying ketamine-induced stress resilience are still largely unknown. Methods Here, we tested if prophylactic ketamine administration altered neural activity in the prefrontal cortex (PFC) and/or hippocampus (HPC). Mice were injected with saline or ketamine (30 mg/kg) one week before social defeat (SD). Following behavioral tests assessing depressive-like behavior, mice were sacrificed and brains were processed to quantify ΔFosB expression. In a second set of experiments, mice were stereotaxically injected with viral vectors into ventral CA3 (vCA3) in order to silence or overexpress ΔFosB prior to prophylactic ketamine administration. In a third set of experiments, ArcCreERT2 mice, a line that allows for the indelible labeling of neural ensembles activated by a single experience, were used to quantify memory traces representing a contextual fear conditioning (CFC) experience following prophylactic ketamine administration. Results Prophylactic ketamine administration increased ΔFosB expression in the ventral dentate gyrus (vDG) and vCA3 of SD mice but not of Ctrl mice. Transcriptional silencing of ΔFosB activity in vCA3 inhibited prophylactic ketamine efficacy, while overexpression of ΔFosB mimicked and occluded ketamine’s prophylactic effects. In the ArcCreERT2 mice, ketamine administration altered memory traces representing the CFC experience in vCA3, but not in vDG. Conclusions Our data indicate that prophylactic ketamine may be protective against a stressor by altering neural activity, specifically the neural ensembles representing an individual stressor in vCA3.
Withdrawal from cocaine self-administration alters the regulation of protein translation in the nucleus accumbens Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-23 Michael T. Stefanik, Mike Milovanovic, Craig T. Werner, John C.G. Spainhour, Marina E. Wolf
Background Cue-induced cocaine craving “incubates” during abstinence from cocaine self-administration. Expression of incubation ultimately depends upon elevation of homomeric GluA1 AMPA receptors (AMPARs) in the nucleus accumbens (NAc). This adaptation requires ongoing protein translation for its maintenance. Aberrant translation is implicated in CNS diseases, but nothing is known about glutamatergic regulation of translation in the drug-naïve NAc or after incubation. Methods NAc tissue was obtained from drug-naïve rats and after 1 or >40 days of abstinence from extended-access cocaine or saline self-administration. Newly translated proteins were labeled using 35S-Met/Cys or puromycin. We compared basal overall translation and its regulation by mGlu1, mGlu5 and NMDA receptors (NMDARs) in naïve, saline and cocaine rats, and compared GluA1 and GluA2 translation by immunoprecipitating puromycin-labeled proteins. Results In all groups, overall translation was unaltered by mGlu1 blockade (LY367385) but increased by mGlu5 blockade (MTEP). NMDAR blockade (APV) increased overall translation in naïve and saline, but not cocaine, rats. Cocaine/late withdrawal rats exhibited greater translation of GluA1 (but not GluA2), which was not further affected by NMDAR blockade. Conclusions Our results suggest that increased GluA1 translation contributes to the elevated homomeric GluA1 AMPAR levels in NAc that mediate incubation. Additional contributions to incubation-related plasticity may result from loss of the braking influence on translation normally exerted by NMDARs. Apart from elucidating incubation-related adaptations, we found a suppressive effect of mGlu5 on NAc translation regardless of drug exposure, which is opposite to results obtained in hippocampus and points to heterogeneity of translational regulation between brain regions.
Metabolism, Metabolomics, and Inflammation in Post-Traumatic Stress Disorder Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-22 Synthia H. Mellon, Aarti Gautam, Rasha Hammamieh, Marti Jett, Owen M. Wolkowitz
Post-traumatic stress disorder (PTSD) is defined by classic psychological manifestations, although among the characteristics are significantly increased rate of serious somatic comorbidities, such as cardiovascular disease, immune dysfunction and metabolic syndrome. In this review, we assess the evidence for disturbances which may contribute to somatic pathology in inflammation, metabolic syndrome, and circulating metabolites (implicating mitochondrial dysfunction) in individuals with PTSD and in animal models simulating features of PTSD. The clinical and preclinical data highlight probable interrelated features of PTSD pathophysiology including a pro-inflammatory milieu, metabolomic changes (implicating mitochondrial and other processes) and metabolic dysregulation. These data suggest that PTSD may be a systemic illness, or at least has systemic manifestations, albeit the behavioral manifestations being the most easily discerned. Whether somatic pathology precedes the development of PTSD (and thus, may be a risk factor) or follows the development of PTSD (either as a result of shared pathophysiologies or lifestyle adaptations), comorbid PTSD and somatic illness is a potent combination placing affected individuals at increased physical as well as mental health risk. We conclude with directions for future research and novel treatment approaches based on these abnormalities.
The GABAB Receptor in Depression and Reward Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-22 Laura H. Jacobson, Styliani Vlachou, David A. Slattery, Xia Li, John F. Cryan
The metabotropic gamma-aminobutyric acid (GABA) receptor, GABAB, was the first described obligate G-protein coupled receptor (GPCR) heterodimer, and continues to set the stage for discoveries in GPRC signaling complexity. In this review, dedicated to the life and work of Athina Markou, we explore the role of GABAB receptors in depression, reward and the convergence of these domains in anhedonia; a shared symptom of major depressive disorder (MDD) and withdrawal from drugs of abuse. GABAB receptor expression and function are enhanced by antidepressants and reduced in animal models of depression. Generally, GABAB receptor antagonists are antidepressant-like and agonists pro-depressive. Exceptions to this rule likely reflect the differential influence of GABAB1 isoforms in depression-related behavior and neurobiology, including the anhedonic effects of social stress. A wealth of data implicate GABAB receptors in the rewarding effects of drugs of abuse. Here we focus on nicotine as an example. GABAB receptor activation attenuates, and deactivation enhances, nicotine reward and associated neurobiological changes. In nicotine withdrawal, however, GABAB receptor agonists, antagonists and positive allosteric modulators (PAMs) enhance anhedonia, perhaps due to differential effects of GABAB1 isoforms on the dopaminergic system. Nicotine cue-induced reinstatement, however, is more reliably attenuated by GABAB receptor activation. Separation of desirable and undesirable side-effects of agonists is achievable with PAMs, which are poised to enter clinical studies for drug abuse. We conclude GABAB1 isoforms are key to understanding the neurobiology of anhedonia, while allosteric modulators may offer a mechanism for targeting specific brain regions and processes associated with reward and depression.
Meeting Report: Can We Make Animal Models of Human Mental Illness? Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-22 Lisa Monteggia, Hakon Heimer, Eric J. Nestler
Modeling aspects of the human condition in animals has provided invaluable information on the physiology of all organ systems as well as assisted in the development of virtually all new therapeutics. Research in cardiovascular disease, cancer, immunology, and others has benefited substantially from the availability of animal models that capture aspects of specific human diseases and that have been used effectively to advance new treatments. By comparison, animal models for neurological and psychiatric disorders have faced several unique obstacles. This essay highlights topics covered in a recent Cold Spring Harbor Laboratory meeting charged with examining the status of animal models for mental illness. The consensus of the conference is that, despite the difficulties inherent with modeling brain disorders in animals, when used judiciously—fully cognizant that models of specific behavioral or biological aspects cannot completely recapitulate the human disorder, animal research is crucial for advancing our understanding of neuropsychiatric disease.
Opposite molecular signatures of depression in men and women Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-31 Marianne L. Seney, Zhiguang Huo, Kelly Cahill, Leon French, Rachel Puralewski, Joyce Zhang, Ryan W. Logan, George Tseng, David A. Lewis, Etienne Sibille
Background Major depressive disorder (MDD) affects women approximately twice as often as men. Women are three times as likely to have atypical depression, with hypersomnia and weight gain. This suggests that the molecular mechanisms of MDD may differ by sex. Methods To test this hypothesis, we performed a large-scale gene expression meta-analysis across three corticolimbic brain regions, the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and basolateral amygdala (N=26 men, 24 women with MDD and sex-matched controls). Results were further analyzed using a threshold-free approach, gene ontology, and cell type-specific analyses. A separate dataset was used for independent validation [N=13 MDD subjects/sex; 22 controls (13 males, 9 females)]. Results Of the 706 genes differentially expressed in men with MDD and 882 genes differentially expressed in women with MDD, only 21 were changed in the same direction in both sexes. Notably, 52 genes displayed expression changes in opposite directions between men and women with MDD. Similar results were obtained using a threshold-free approach, where the overall transcriptional profile of MDD was opposite in men and women. Gene ontology indicated that men with MDD had decreases in synapse-related genes, whereas women with MDD exhibited transcriptional increases in this pathway. Cell type-specific analysis indicated that men with MDD exhibited increases in oligodendrocyte- and microglia-related genes, while women with MDD had decreases in markers of these cell types. Conclusions The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.
Distinct proteomic, transcriptomic and epigenetic stress-responses in dorsal and ventral hippocampus Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-16 Amalia Floriou-Servou, Lukas von Ziegler, Luzia Stalder, Oliver Sturman, Mattia Privitera, Anahita Rassi, Alessio Cremonesi, Beat Thöny, Johannes Bohacek
Background Acutely stressful experiences can trigger neuropsychiatric disorders and impair cognitive processes, by altering hippocampal function. Although the intrinsic organization of the hippocampus is highly conserved throughout its long dorsal-ventral axis, the dorsal (anterior) hippocampus mediates spatial navigation and memory formation, whereas the ventral (posterior) hippocampus is involved in emotion regulation. To understand the molecular consequences of stress, detailed genome-wide screens are necessary and need to distinguish between dorsal and ventral hippocampus. While transcriptomic screens have become a mainstay in basic and clinical research, proteomic methods are rapidly evolving and hold even greater promise to reveal biologically and clinically relevant biomarkers. Methods Here, we provide the first combined transcriptomic (RNA-seq) and proteomic (SWATH-MS) profiling of dorsal and ventral hippocampus in mice. We use three different acute stressors (novelty, swim, restraint) to assess the impact of stress on both regions. Results We demonstrate that both hippocampal regions display radically distinct molecular responses, and that the ventral hippocampus is particularly sensitive to the effects of stress. Separately analyzing these structures greatly increases the sensitivity to detect stress-induced changes. For example, protein-interaction cluster analyses reveal a stress-responsive epigenetic network around histone demethylase Kdm6b restricted to the ventral hippocampus, and acute stress reduces methylation of its enzymatic target H3K27me3. Selective Kdm6b knockdown in the ventral hippocampus leads to behavioral hyperactivity/hyper-responsiveness. Conclusions These findings underscore the importance of considering dorsal and ventral hippocampus separately when conducting high-throughput molecular analyses, which has important implications for fundamental research as well as clinical studies.
Default mode connectivity in major depressive disorder measured up to 10 days after ketamine administration Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-15 Jennifer W. Evans, Joanna Szczepanik, Nancy Brutsché, Lawrence T. Park, Allison C. Nugent, Carlos A. Zarate Jr.
Background The symptoms of major depressive disorder (MDD) are rapidly alleviated by administration of a single dose of the glutamatergic modulator ketamine. However, few studies have investigated the potential sustained neural effects of this agent beyond immediate infusion. This study used functional magnetic resonance imaging (fMRI) to examine the effect of a single ketamine infusion on the resting state default mode network (DMN) at two and 10 days after a single ketamine infusion in unmedicated MDD subjects as well as healthy controls (HCs). Methods Data were drawn from a double-blind, placebo-controlled, crossover study of 58 participants (33 with MDD and 25 HCs) who received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on two separate test days spaced two weeks apart. Eight minutes of fMRI resting state data were acquired at baseline and at about two and 10 days after both infusions. The DMN was defined using seed-based correlation and compared across groups and scans. Results In MDD subjects, connectivity between the insula and the DMN was normalized compared to HCs two days post-ketamine infusion. This change was reversed after 10 days and did not appear in either of the placebo scans. Group-specific connectivity differences in drug response were observed, most notably in the insula in MDD subjects and the thalamus in HCs. Conclusions Connectivity changes in the insula in MDD subjects suggest that ketamine may normalize the interaction between the DMN and salience networks, supporting the triple network dysfunction model of MDD. NCT#00088699; https://clinicaltrials.gov/ct2/show/NCT00088699
Increased alcohol seeking in mice lacking Gpr88 involves dysfunctional mesocorticolimbic networks Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-09 Sami Ben Hamida, Sueli Netto, Tanzil Mahmud Arefin, Md. Taufiq Nasseef, Laura-Joy Boulos, Michael McNicholas, Aliza Toby Ehrlich, Eleanor Clarke, Luc Moquin, Alain Gratton, Emmanuel Darcq, Harsan Laura Adela, Rafael Maldonado, Brigitte Lina Kieffer
Backgound. Alcohol Use Disorders (AUDs) are devastating and poorly treated, and innovative targets are actively sought for prevention and treatment. The orphan G protein-coupled receptor GPR88 is enriched in mesocorticolimbic pathways, and Gpr88 knockout mice show hyperactivity and risk-taking behavior, but a potential role for this receptor in drug abuse has not been examined. Methods We tested Gpr88 knockout mice for alcohol drinking and seeking behaviors. To gain system-level understanding of their alcohol endophenotype, we also analyzed whole-brain functional connectivity (FC) in naïve mice using resting-state functional magnetic resonance imaging. Results Gpr88 knockout mice showed increased voluntary alcohol drinking at both moderate and excessive levels, with intact alcohol sedation and metabolism. Mutant mice also showed increased operant responding and motivation for alcohol, while food and chocolate operant self-administration were unchanged. Alcohol place conditioning and alcohol-induced dopamine release in the nucleus accumbens (NAC) were decreased, suggesting reduced alcohol reward in mutant mice that may partly explain enhanced alcohol drinking. Seed-based voxelwise FC analysis revealed significant remodeling of mesocorticolimbic centers, whose hallmark was predominant weakening of prefrontal cortex, ventral tegmental area (VTA) and amygdala (AMY) connectional patterns. Also, effective connectivity from VTA to NAC and AMY was reduced. Conclusion Gpr88 deletion disrupts executive, reward and emotional networks in a configuration that reduces alcohol reward and promotes alcohol seeking and drinking. The FC signature is reminiscent of alterations observed in individuals at-risk for AUDs. The Gpr88 gene, therefore, may represent a vulnerability/resilience factor for AUDs, and a potential drug target for AUDs treatment.
Habits are negatively regulated by histone deacetylase 3 in the dorsal striatum Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-08 Melissa Malvaez, Venuz Y. Greenfield, Dina P. Matheos, Nicolas A. Angelillis, Michael D. Murphy, Pamela J. Kennedy, Marcelo A. Wood, Kate. M. Wassum
Background Optimal behavior and decision making result from a balance of control between two strategies, one cognitive/goal-directed and one habitual. These systems are known to rely on the anatomically distinct dorsomedial (DMS) and dorsolateral (DLS) striatum, respectively. But the transcriptional regulatory mechanisms required to learn and transition between these strategies are unknown. Here we examined the role of one chromatin-based transcriptional regulator, histone modification via histone deacetylases (HDACs), in this process. Methods To do this, we combined procedures that diagnose behavioral strategy in rats with pharmacological and viral-mediated HDAC manipulations, chromatin immunoprecipitation, and mRNA quantification. Results The results indicate that dorsal striatal HDAC3 activity constrains habit formation. Systemic HDAC inhibition following instrumental (lever press→reward) conditioning increased histone acetylation throughout the dorsal striatum and accelerated habitual control of behavior. HDAC3 was removed from the promoters of key, CREB-regulated, learning-related genes in the dorsal striatum as habits formed with overtraining and with post-training HDAC inhibition. Decreasing HDAC3 function, either by selective pharmacological inhibition or expression of dominant-negative mutated HDAC3, in either the DLS or DMS accelerated habit formation, while HDAC3 overexpression in either region prevented habit. Conclusions These results challenge the strict dissociation between DMS and DLS function in goal-directed v. habitual behavioral control and identify dorsal striatal HDAC3 as a critical molecular directive of the transition to habit. Because this transition is disrupted in many neurodegenerative and psychiatric diseases, these data suggest a potential molecular mechanism for the negative behavioral symptoms of these conditions and a target for therapeutic intervention.
A Mitochondrial Health Index Sensitive to Mood and Caregiving Stress Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-03 Martin Picard, Aric A. Prather, Eli Puterman, Alexanne Cuillerier, Michael Coccia, Kirstin Aschbacher, Yan Burelle, Elissa Epel
Background Chronic life stress, such as the stress of caregiving, can promote pathophysiology, but the underlying cellular mechanisms are not well understood. Chronic stress may induce recalibrations in mitochondria leading to either changes in mitochondrial content per cell, or in mitochondrial functional capacity (i.e., quality). Methods Here we present a functional index of mitochondrial health (MHI) for human leukocytes that can distinguish between these possibilities. The MHI integrates nuclear- and mitochondrial DNA (mtDNA)-encoded respiratory chain enzymatic activities and mtDNA copy number. We then use the MHI to test the hypothesis that caregiving stress and daily emotional states influence mitochondrial function by comparing healthy mothers of either a child with an autism spectrum disorder (high stress caregivers, n=46) or with a neurotypical child (control group, n=45). Results The MHI outperformed individual mitochondrial function measures. Elevated positive mood at night was associated with higher MHI, and nightly positive mood was also a mediator of the association between caregiving and MHI. Moreover, MHI was correlated to positive mood on the days preceding, but not following the blood draw, suggesting for the first time in humans that mitochondria may respond to proximate emotional states within days. Correspondingly, the caregiver group, which had higher perceived stress, lower positive and greater negative daily affect, exhibited lower MHI. This effect was not explained by a mismatch between nuclear and mitochondrial genomes. Conclusions Daily mood and chronic caregiving stress are associated with mitochondrial functional capacity. Mitochondrial health may represent a nexus between psychological stress and health.
Insula-Retrosplenial Cortex Overconnectivity Increases Internalizing Via Reduced Insight in Autism Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-31 Jeremy Hogeveen, Marie K. Krug, Matthew V. Elliott, Marjorie Solomon
Background Internalizing symptoms like anxiety and depression are common and impairing in autism spectrum disorder (ASD). Here, we test the hypothesis that aberrant functional connectivity between three brain networks [salience network (SN), default-mode network (DMN), and frontoparietal network (FPN)] plays a role in the pathophysiology of internalizing in ASD. Methods We examined the association between resting-state functional connectivity and internalizing in 102 adolescents and young adults with ASD (N=49) or typical development (TYP; N=53). Seed-to-target functional connectivity was contrasted between ASD and TYP using a recent parcellation of the human cerebral cortex, and connections that were aberrant in ASD were analyzed dimensionally as a function of parent-reported internalizing symptoms. Results Three connections demonstrated robust overconnectivity in ASD: i) anterior insula to retrosplenial cortex (i.e. SN-DMN), ii) anterior insula to frontal pole (i.e. SN-FPN), and iii) dorsolateral prefrontal cortex to retrosplenial cortex (i.e. FPN-DMN). These differences remained significant after controlling for age, and no age-related effects survived correction. The SN-DMN connection was associated with greater internalizing in ASD, mediated by a bigger difference between self- and parent-reported internalizing. Control analyses found that the other two connections were not associated with internalizing, and SN-DMN connectivity was not associated with a well-matched control measure (externalizing symptoms). Conclusions The present findings provide novel evidence for a specific link between SN-DMN overconnectivity and internalizing in ASD. Further, the mediation results suggest that intact anterior insula-retrosplenial connectivity may play a role in generating insight into ones’ own psychopathology.
Presynaptic effects of NMDA receptors enhance parvalbumin cell-mediated inhibition of pyramidal cells in mouse prefrontal cortex Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-31 Diego E. Pafundo, Takeaki Miyamae, David A. Lewis, Guillermo Gonzalez Burgos
Background Testing hypotheses regarding the role of N-methyl-D-aspartate receptor (NMDAR) hypofunction in schizophrenia requires understanding the mechanisms of NMDAR regulation of prefrontal cortex (PFC) circuit function. NMDAR antagonists are thought to produce pyramidal cell (PC) disinhibition. However, inhibitory parvalbumin-positive basket cells (PVBCs) have modest NMDAR-mediated excitatory drive, and thus are unlikely to participate in NMDAR antagonist-mediated disinhibition. Interestingly, recent studies demonstrated that presynaptic NMDARs enhance transmitter release at central synapses. Thus, if presynaptic NMDARs enhance GABA release at PVBC-to-PC synapses, they could participate in NMDAR-dependent PC disinhibition. Here, we examined if presynaptic NMDAR effects could modulate GABA release at PVBC-to-BC synapses in mouse PFC. Methods Using whole-cell recordings from synaptically-connected pairs in mouse PFC, we determined if NMDA or NMDAR antagonist application affects PVBC-to-PC inhibition in a manner consistent with a presynaptic mechanism. Results NMDAR activation enhanced by ∼40% the synaptic current at PVBC-to-PC pairs. This effect was consistent with a presynaptic mechanism, since it was 1) observed with postsynaptic NMDARs blocked by intracellular MK801, 2) associated with lower rate of transmission failures and higher transmitter release probability, and 3) blocked by intracellular MK801 in the PVBC. NMDAR antagonist application did not affect the synaptic currents in PVBC-to-PC pairs, but reduced the inhibitory currents elicited in PCs with simultaneous glutamate release by extracellular stimulation. Conclusions We demonstrate that NMDAR activation enhances PVBC-to-PC inhibition in a manner consistent with presynaptic mechanisms, and suggest that the functional impact of this presynaptic effect depends on the activity state of the PFC network.
Air pollution exposure during fetal life, brain morphology, and cognitive function in school-age children Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-31 Mònica Guxens, Małgorzata J. Lubczyńska, Ryan Muetzel, Albert Dalmau-Bueno, Vincent W.V. Jaddoe, Gerard Hoek, Aad van der Lugt, Frank C. Verhulst, Tonya White, Bert Brunekreef, Henning Tiemeier, Hanan El Marroun
Objective Air pollution exposure during fetal life has been related to impaired child neurodevelopment but it is unclear if brain structural alterations underlie this association. The authors assessed whether air pollution exposure during fetal life alters brain morphology and whether these alterations mediate the association between air pollution exposure during fetal life and cognitive function in school-age children. Method We used data from a population-based birth cohort set up in Rotterdam, The Netherlands (2002-2006). Residential levels of air pollution during the entire fetal period were calculated using land-use regression models. Structural neuroimaging and cognitive function were performed at age 6-10 years (n=783). Models were adjusted for several socioeconomic and life-style characteristics. Results Mean fine particle levels were 20.2μg/m3 (range 16.8-28.1). Children exposed to higher particulate matter levels during fetal life had thinner cortex in several brain regions of both hemispheres (e.g. cerebral cortex of the precuneus region in the right hemisphere was 0.045mm thinner (95% Confidence Interval 0.028-0.062) for each 5μg/m3 increase in fine particles). The reduced cerebral cortex in precuneus and rostral middle frontal regions partially mediated the association between exposure to fine particles and impaired inhibitory control. Air pollution exposure was not associated with global brain volumes. Conclusions Exposure to fine particles during fetal life was related to child brain structural alterations of the cerebral cortex and these alterations partially mediated the association between exposure to fine particles during fetal life and impaired child inhibitory control. Such cognitive impairment at early ages could have significant long-term consequences.
Dose-related target occupancy and effects on circuitry, behavior, and neuroplasticity of the glycine transporter-1 inhibitor, PF-03463275, in healthy and schizophrenia subjects Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-31
Background Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia (CIAS). The dose-related occupancy and target engagement of the GlyT1 inhibitor, PF-03463275 were studied to inform optimal dose selection for a clinical trial for CIAS. Methods In substudy #1, the effects of PF-03463275 (10, 20, and 40 mg BID) on occupancy of GlyT1 were tested using PET and 18F-MK-6577, and visual long-term potentiation (LTP) in schizophrenia patients (SZS) and healthy subjects (HSs). Furthermore, the capacity of PF-03463275 to attenuate ketamine-induced disruption of working memory-related activation of a “working memory” circuit was tested only in HSs using fMRI. Subsequently, the effects of PF-03463275 (60 mg BID) on occupancy of GlyT1 and LTP were examined only in SZs (substudy #2). Results PF-03463275, 10 mg, 20 mg, 40 mg, and 60 mg BID produced ∼44%, 61%, 76%, and 83% GlyT1 occupancy respectively in SZs with higher ligand binding to GlyT1 in subcortical versus cortical regions. PF-03463275 did not attenuate any ketamine-induced effects but did improve working memory accuracy in HSs. PF-03463275 increased LTP only in SZs with peak effects at 40 mg BID (∼75% GlyT1 occupancy) and with a profile suggestive of an inverted ‘U’ dose response. PF-03463275 was well-tolerated. Conclusions The dose-related GlyT1 occupancy of PF-03463275 is linear. While PF-03463275 did not show evidence of facilitating NMDA-R function in the ketamine assay, it enhanced neuroplasticity in SZs. Together, these findings provide support for a clinical trial to test the ability of PF-03463275 to enhance CR towards addressing CIAS. ClinicalTrials.gov (NCT01911676)
Effective use of animal models for therapeutic development in psychiatric and substance use disorders Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-31 Anthony G. Phillips, Mark A. Geyer, Trevor W. Robbins
Athina Markou and others argue forcefully for the adoption of a “translational-back translational strategy” for CNS drug discovery involving novel application of drugs with established safety profiles in proof of principle studies in humans, which in turn encourage parallel studies using experimental animals to provide vital data on the neural systems and neuropharmacological mechanisms related to the actions of the candidate drugs. Encouraged by the increasing adoption of drug development strategies involving reciprocal information exchange between preclinical animal studies and related clinical research programs, this review presents additional compelling examples related to 1), the treatment of cognitive deficits that define Attention Deficit Hyperactivity Disorder; 2), the development of fast-acting antidepressants based on promising clinical effects with low doses of the anesthetic ketamine; 3), new and effective medications for the treatment of substance misuse. In the context of addressing the unmet medical need for new and effective drugs for treatment of mental ill-health, now may be the time to launch major new academic-industry consortia committed to open-access of all preclinical and clinical data generated by this research.
Essential role of ovarian hormones in susceptibility to the consequences of witnessing social defeat in female rats Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-31 Julie E. Finnell, Brandon L. Muniz, Akhila R. Padi, Calliandra M. Lombard, Casey M. Moffitt, Christopher S. Wood, L. Britt Wilson, Lawrence P. Reagan, Marlene A. Wilson, Susan K. Wood
Background Women are at greater risk of developing depression and comorbid disorders such as cardiovascular disease compared with men. This enhanced risk begins at puberty and ends following menopause, suggesting a role for ovarian hormones in this sensitivity. Here, we used a model of psychosocial witness stress for the first time in female rats to determine the stress-induced neurobiological adaptations that underlie stress susceptibility in an ovarian hormone dependent manner. Methods Female rats (intact or ovariectomized, OVX) were exposed to 5 daily 15-minute witness stress exposures. Witness stress-evoked burying, behavioral despair, and anhedonia were measured. Cardiovascular telemetry was combined with plasma measurements of inflammation, epinephrine and corticosterone as indices of cardiovascular dysfunction. Finally, interleukin-1β (IL-1β) and corticotropin releasing factor (CRF) were assessed in the central amygdala (CeA). Results Witness stress produced anxiety-like burying, depressive-like anhedonia and behavioral despair selectively in intact females, which was associated with enhanced sympathetic responses during stress including increased blood pressure, heart rate, and arrhythmias. Moreover, intact females exhibited increases in 12-hr resting systolic pressure and heart rate and reductions in heart rate variability. Notably, OVX females remained resilient. Moreover intact, but not OVX, females exposed to witness stress exhibited a sensitized cytokine and epinephrine response to stress and distinct increases in CRF and IL-1β in the CeA. Conclusions Together these data suggest that ovarian hormones play a critical role in the behavioral, inflammatory and cardiovascular susceptibility to social stress in females and reveal putative systems that are sensitized to stress in an ovarian hormone-dependent manner.
Genomic Approaches to Posttraumatic Stress Disorder: the Psychiatric Genomic Consortium Initiative Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-02 Caroline M. Nievergelt, Allison E. Ashley-Koch, Shareefa Dalvie, Michael A. Hauser, Rajendra A. Morey, Alicia K. Smith, Monica Uddin
Post-traumatic stress disorder (PTSD) after exposure to a traumatic event is a highly prevalent psychiatric disorder. Heritability estimates from twin studies as well as from recent molecular data (h2SNP) indicate moderate to high heritability, yet robust genetic variants for PTSD have not yet been identified and the genetic architecture of this polygenic disorder remains largely unknown. To date, less than ten large-scale genome-wide association studies (GWAS) of PTSD have been published, with findings that highlight the unique challenges for PTSD genomics, including a complex diagnostic entity with contingency of PTSD diagnosis on trauma exposure, and the large genetic diversity of the study populations. The Psychiatric Genomics Consortium PTSD group (PGC-PTSD) has brought together over 200 scientists with the goal to increase sample size for GWAS and other genomic analyses to sufficient numbers where robust discoveries of molecular signatures can be achieved. The sample currently includes over 32,000 PTSD cases and 100,000 trauma-exposed controls and collection is ongoing. First results found a significant shared genetic risk of PTSD with other psychiatric disorders, and sex-biased heritability estimates with higher heritability in females compared to males. This review describes the scope and current focus of the PGC-PTSD, and its expansion from the initial GWAS group to nine working groups, including epigenetics, gene expression, imaging, and integrative systems biology. We further briefly outline recent findings and future directions of ‘omics-based’ studies of PTSD, with the ultimate goal of elucidating the molecular architecture of this complex disorder to improve prevention and intervention strategies.
Dopamine D1 receptor positive neurons in the lateral nucleus of the cerebellum contribute to cognitive behavior Biol. Psychiatry (IF 11.412) Pub Date : 2018-02-02 Timothy M. Locke, Marta E. Soden, Samara M. Miller, Avery Hunker, Cerise Knakal, Julia A. Licholai, Karn S. Dhillon, C. Dirk Keene, Larry S. Zweifel, Erik S. Carlson
Background Studies in humans and non-human primates have identified a region of the dentate nucleus of the cerebellum (DCN), or lateral nucleus in rodents (LCN), activated during performance of cognitive tasks involving complex spatial and sequential planning. Whether such a subdivision exists in the rodent is not known. Dopamine and its receptors, which are implicated in cognitive function, are present in the cerebellar nuclei but their function is unknown. Methods Utilizing viral and genetic strategies in mice, we examined cellular phenotypes of dopamine D1 receptor positive (D1R+) cells in the LCN with whole-cell patch clamp recordings, mRNA profiling, and immunohistochemistry to examine D1R expression in mouse LCN and human DCN. We used chemogenetics to inhibit D1R+ neurons, and examined behaviors including spatial navigation, social recognition memory, prepulse inhibition of the acoustic startle reflex (PPI), response inhibition, and working memory to test the necessity of these neurons in these behaviors. Results We identified a population of D1R+ neurons that are localized to an anatomically distinct region of the LCN. We also observed D1R+ neurons in the human DCN, suggesting an evolutionarily conserved population of dopamine-receptive neurons in this region. The genetic, electrophysiological, and anatomical profile of mouse D1R neurons is consistent with a heterogeneous population of GABAergic, and to a lesser extent glutamatergic cell types. Selective inhibition of D1R+ LCN neurons impairs spatial navigation memory, response inhibition, working memory, and PPI. Conclusion Collectively, these data demonstrate a functional link between genetically distinct neurons in the LCN and cognitive behaviors.
Combined Analysis of Mifepristone for Psychotic Depression; Plasma Levels Associated with Clinical Response Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-31 Thaddeus Block, Harvey Kushner, Ned Kalin, Craig Nelson, Joseph Belanoff, Alan Schatzberg
Background Patients with Psychotic Depression (PD) exhibit elevated cortisol levels. Competitively antagonizing cortisol at the glucocorticoid receptor (GR) with mifepristone demonstrated therapeutic benefit in early studies of patients with PD. We present a combined analysis of all controlled Phase 2/3 studies to report antipsychotic differences between treatment with mifepristone or placebo and to evaluate the relative contributions to response of attaining an a priori–defined, high-mifepristone plasma level and markers of GR antagonism (increases in ACTH and cortisol) with treatment. Methods Data from five similarly designed double-blind Phase 2 or 3 studies evaluating the efficacy and safety of 7-day treatment with mifepristone for the psychotic symptoms of PD were pooled for analysis (mifepristone n=833, placebo n=627). Clinical assessments were performed at baseline and Days 7, 14, 28, 42, and 56. Mifepristone, ACTH and cortisol samples were collected at baseline and Day 7. Results Combined results demonstrated meaningful efficacy (p<.004) for mifepristone in reducing psychotic symptoms with wide safety margins. Patients in the a priori–defined, high-mifepristone-plasma-level group (High-PL) – greater than or equal to 1637 ng/mL – demonstrated a more significant treatment effect over placebo (p=0.0004). A Number Needed to Treat (NNT) of 7 and 48 was observed in the High-PL group and Low-PL (low mifepristone plasma level group), respectively. Adverse events were similar in mifepristone and placebo treated patients. Conclusion High-PL carried the strongest association with response, followed by changes in ACTH and cortisol. Therapeutic plasma levels of mifepristone were most likely to be achieved with the 1200 mg/d dose. ClinicalTrials.gov Registry: NCT00130676, NCT00146523, NCT00128479, NCT00637494
α-synuclein oligomers induce a unique toxic tau strain Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-17 Diana L. Castillo-Carranza, Marcos J. Guerrero-Muñoz, Urmi Sengupta, Julia E. Gerson, Rakez Kayed
Background The coexistence of α-synuclein and tau aggregates in several neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD), raises the possibility that a seeding mechanism is involved in disease progression. Methods To further investigate the role of α-synuclein in the tau aggregation pathway, we performed a set of experiments using both recombinant and brain-derived tau and α-synuclein oligomers to seed monomeric tau aggregation in vitro and in vivo. Brain-derived tau oligomers were isolated from well characterized cases of progressive supranuclear palsy (PSP, n=4) and complexes of brain-derived α-synuclein/tau oligomers isolated from PD (n=4) cases. The isolated structures were purified and characterized by standard biochemical methods then injected in Htau mice (n=24) to assess their toxicity and role in the tau aggregation. Results Here, we found that α-synuclein induced a distinct toxic tau oligomeric strain that avoids fibril formation. In vivo, PD α-synuclein/tau oligomers administered into Htau mouse brains accelerated endogenous tau oligomer formation concurrent with increasing cell loss. Conclusion Our findings provide evidence, for the first time, that α-synuclein enhances the harmful effects of tau, thus contributing to disease progression.
Dynamic changes of the mitochondria in psychiatric illnesses: new mechanistic insights from human neuronal models Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-17 Rupali Srivastava, Travis Faust, Adriana Ramos, Koko Ishizuka, Akira Sawa
Mitochondria play a crucial role in neuronal function, especially in energy production, generation of reactive oxygen species, and calcium signaling. Multiple lines of evidence have suggested possible involvement of mitochondrial deficits in major psychiatric disorders, such as schizophrenia and bipolar disorder. In the first half, this review will outline the current understanding of the physiological role of mitochondria and their dysfunction under pathological conditions, particularly in psychiatric disorders. Nevertheless, the current knowledge about mitochondrial deficits in these disorders is somewhat limited, due to the lack of effective methods to dissect dynamic changes in the functional deficits that are directly associated with psychiatric conditions. Human neuronal cell model systems, which have been dramatically developed in recent years through the use of stem cell technology, may be key tools for overcoming this dilemma and improving our understanding of the dynamic changes in the mitochondrial deficits in patients with psychiatric disorders. We introduce recent discoveries from new experimental models and conclude the discussion by referring to future perspectives. In the perspectives, we emphasize the significance of combining studies of human neuronal cell models with those of other experimental systems, including animal models.
Glutamatergic ventral pallidal neurons modulate activity of the habenula - tegmental circuitry and constrain reward seeking Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-12 Jessica Tooley, Lauren Marconi, Jason Alipio, Bridget Matikainen-Ankney, Polymnia Georgiou, Alexxai V. Kravitz, Meaghan C. Creed
Background The ability to appropriately integrate and respond to rewarding and aversive stimuli is essential for survival. The ventral pallidum (VP) plays a critical role in processing both rewarding and aversive stimuli. However, the VP is a heterogeneous structure, and how VP subpopulations integrate into larger reward networks to ultimately modulate these behaviors is not known. We identify a non-canonical population of glutamatergic VP neurons that play a unique role in responding to aversive stimuli and constraining inappropriate reward seeking. Methods Using neurochemical, genetic and electrophysiology approaches, we characterized glutamatergic VP neurons (4-8 mice/group). We performed patch clamp and in vivo electrophysiology recordings in the LHb, RMTg and VTA to determine the effect of glutamatergic VP neuron activation in these target regions (6-10 mice/group). Finally, we selectively optogenetically stimulated glutamatergic VP neurons in an RTPP task, and ablated these neurons using a virally-expressed caspase to determine their necessity for reward seeking. Results Glutamatergic VP neurons exhibit little overlap with cholinergic or GABAergic markers, the canonical VP subtypes, and exhibit distinct membrane properties. Glutamatergic VP neurons innervate and increase firing activity of LHb, RMTg and GABAergic VTA neurons. While non-selective optogenetic stimulation of the VP induced a robust place preference, selective activation of glutamatergic VP neurons induced a place avoidance. Viral ablation of glutamatergic VP neurons increased reward responding and abolished taste aversion to sucrose. Conclusions Glutamatergic VP neurons constitute a non-canonical subpopulation of VP neurons. These glutamatergic VP neurons increase activity of the LHb, RMTg and GABAergic VTA neurons and adaptively constrain reward seeking.
Psychiatric symptom dimensions are associated with dissociable shifts in metacognition but not task performance Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-11 Marion Rouault, Tricia Seow, Claire M. Gillan, Stephen M. Fleming
Background Distortions in metacognition – the ability to reflect upon and control other cognitive processes – are thought to be characteristic of poor mental health. However, it remains unknown whether such shifts in self-evaluation are due to specific alterations in metacognition and/or a downstream consequence of changes in decision-making processes. Methods Using perceptual decision-making as a model system, we employed a computational psychiatry approach to relate parameters governing both decision formation and metacognitive evaluation to self-reported transdiagnostic symptom dimensions in a very large general population sample (N=995). Results Variability in psychopathology was unrelated to either speed or accuracy of decision formation. In contrast, leveraging a dimensional approach, we reveal independent relationships between psychopathology and metacognition: a symptom dimension related to anxiety and depression was associated with lower confidence and heightened metacognitive efficiency, whereas a dimension characterizing compulsive behavior and intrusive thoughts was associated with higher confidence and lower metacognitive efficiency. Furthermore, we obtain a robust double dissociation – while psychiatric symptoms predicted changes in metacognition but not decision performance, age predicted changes in decision performance but not metacognition. Conclusions Our findings indicate a specific and pervasive link between metacognition and mental health. Our study bridges a gap between an emerging neuroscience of decision-making and an understanding of metacognitive alterations in psychopathology.
Genome-wide association study identifies a regulatory variant of RGMA associated with opioid dependence in European Americans Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-11 Zhongshan Cheng, Hang Zhou, Richard Sherva, Lindsay Farrer, Henry R. Kranzler, Joel Gelernter
Background Opioid dependence (OD) is at epidemic levels in the United States. Genetic studies can provide insight into its biology. Methods We completed an OD genome-wide association study (GWAS) in 3058 opioid-exposed European-Americans, 1290 of whom met criteria for a DSM-IV diagnosis of OD. Analysis used DSM-IV criterion count. Results By meta-analysis of four cohorts, Yale-Penn 1 (n=1388), Yale-Penn 2 (n=996), Yale-Penn 3 (n=98) and SAGE (n=576), we identified a variant on chromosome 15, rs12442183, near RGMA (repulsive guidance molecule A (RGMa)), associated with OD (P=1.3×10-8). The association was also genome-wide significant (GWS) in Yale-Penn 1 taken individually, and nominally significant in two of the other three samples. The finding was further supported in a meta-analysis of all available opioid-exposed African-Americans (n=2014, 1106 meeting DSM-IV OD criteria; P=3.0×10-3) from three cohorts; there was nominal significance in two of these samples. Thus, of the seven subsamples examined in two populations, one was GWS and four of six were nominally significant. RGMa is a CNS axon guidance protein. Risk allele rs12442183*T was correlated with higher expression of a specific RGMA transcript variant in frontal cortex (P=2×10-3). After chronic morphine injection, the homologous mouse gene (Rgma) was upregulated in C57BL/6J striatum. Co-expression analysis of 1301 brain samples revealed that RGMA mRNA expression was associated with that of four genes implicated in other psychiatric disorders, including GRIN1. Conclusion This is the first study to demonstrate an association of RGMA with OD. It provides a new lead into our understanding of OD pathophysiology.
Neurogenetic Approaches to Stress and Fear in Humans as Pathophysiological Mechanisms for Posttraumatic Stress Disorder Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-10 Frauke Nees, Stephanie H. Witt, Herta Flor
In this review article, genetic variation associated with brain responses related to acute and chronic stress reactivity and fear learning in humans is presented as important mechanism underlying posttraumatic stress disorder (PTSD). We report that genes related to the regulation of the hypothalamus-pituitary-adrenal axis as well as genes that modulate serotonergic, dopaminergic, and neuropeptergic functions or plasticity, play a role in this context. The strong overlap of the genetic targets involved in stress and fear learning suggests that a dimensional and mechanistic model of the development of PTSD based on these constructs is promising. Genome-wide genetic analyses on fear and stress mechanisms are scarce. So far, reliable replication is still lacking for most of the molecular genetic findings and the proportion of explained variance is rather small. Further analysis of neurogenetic stress and fear learning needs to integrate data from animal and human studies.
Peroxisome Proliferator Activated Receptor Gamma Co-activator-1 Alpha as a Novel Target for Bipolar Disorder and other Neuropsychiatric Disorders Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-10 Andrew A. Nierenberg, Sharmin A. Ghaznavi, Isadora Sande Mathias, Kristen K. Ellard, Jessica A. Janos, Louisa G. Sylvia
Peroxisome Proliferator Activated Receptor Gamma Coactivator-1 alpha (PGC-1 alpha) is a protein that regulates metabolism and inflammation by activating nuclear receptors, especially the family of Peroxisome Proliferator Activated Receptors (PPARs). PGC-1 alpha and PPARs also regulate mitochondrial biogenesis, cellular energy production, thermogenesis, and lipid metabolism. Brain energy metabolism may also be, in part, regulated by the interaction between PGC-1 alpha and PPARs. Because neurodegenerative diseases (Huntington’s Disease, Parkinson’s Disease, and amyotrophic lateral sclerosis) and bipolar disorder have been associated with dysregulated mitochondrial and brain energy metabolism, PGC-1 alpha may represent a potential drug target for these conditions. The purpose of this paper is to review the physiology of PGC-1 alpha, PPARs, and the role of PPAR agonists to target PGC-1 alpha to treat neurodegenerative diseases and bipolar disorder. We also review clinical trials of repurposed anti-diabetic thiazolidines and anti-triglyceride fibrates (PPAR agonists) for neurodegenerative diseases and bipolar disorder. PGC-1 alpha and PPARs are innovative potential targets for bipolar disorder, and warrant future clinical trials.
Genes and pathways regulated by androgens in human neural cells, potential candidates for the male excess in autism spectrum disorders Biol. Psychiatry (IF 11.412) Pub Date : 2018-01-09 Angélique Quartier, Laure Chatrousse, Claire Redin, Céline Keime, Nicolas Haumesser, Anne Maglott-Roth, Laurent Brino, Stéphanie Le Gras, Alexandra Benchoua, Jean-Louis Mandel, Amélie Piton
Background Prenatal exposure to androgens during brain development in males may participate to increase their susceptibility to develop neurodevelopmental disorders (ND) such as autism spectrum disorders (ASD) or intellectual disability (ID). However, little is known about the action of androgens in human neural cells. Methods: We used human neural precursors (hNSCs) differentiated from embryonic stem cells to investigate targets of androgens. Results RNA-sequencing revealed that treatment with dihydroxytestosterone (DHT) leads to subtle but significant changes in the expression of about two hundred genes, encoding proteins of extracellular matrix or involved in signal transduction of growth factors (insulin/IGF1, etc). We showed that the most differentially expressed genes (DEGs), RGCC, RNF144B, NRCAM, TRIM22, FAM107A, IGFBP5 and LAMA2, are reproducibly regulated by different androgens in different genetic backgrounds. We showed, by overexpressing the Androgen receptor (AR) in neuroblastoma cells SH-SY5Y or knocking it down in hNSCs that this regulation involves the AR. A ChIP-Seq analysis identified AR-bound sequences in almost half of the DHT-DEGs and in numerous other genes. DHT-DEGs appear enriched in genes involved in ASD (ASXL3, NLGN4X, etc), associated with ASD (NRCAM), or differentially expressed in patients with ASD (FAM107A, IGFBP5). Androgens increase hNSCs proliferation and survival in nutrient-deprived culture conditions, with no detectable effect on regulation of neurite outgrowth. Conclusions We characterized androgen action in neural progenitor cells, identifying DHT-DEGs which appear to be enriched in genes related to ASD. We also showed that androgens increase neuronal precursor proliferation and protect them from death during their differentiation in nutrient-deprived conditions.
Role of dorsal striatal histone deacetylase 5 in incubation of methamphetamine craving Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-29 Xuan Li, Maria B. Carreria, Kailyn F.R. Witonsky, Tamara Zeric, Olivia M. Lofaro, Jennifer M. Bossert, Jianjun Zhang, Felicia Surjono, Christopher T. Richie, Brandon K. Harvey, Hyeon Son, Christopher W. Cowan, Eric J. Nestler, Yavin Shaham
Background Methamphetamine (Meth) seeking progressively increases after withdrawal (incubation of Meth craving). We previously demonstrated an association between histone deacetylase 5 (HDAC5) gene expression in rat dorsal striatum and incubation of Meth craving. Here we used viral constructs to study the causal role of dorsal striatal HDAC5 in this incubation. Methods In Exp. 1 (over-expression), we injected adeno-associated virus (AAV) bilaterally into dorsal striatum to express either GFP (control) or a mutant form of HDAC5 (mHDAC5), which strongly localized to the nucleus. After training rats to self-administer Meth (10 days, 9 h/d), we tested the rats for relapse to Meth seeking on withdrawal days 2 and 30. In Exp. 2 (knockdown), we injected AAV bilaterally into dorsal striatum to express either a short hairpin RNA against luciferase (shLUC, control) or against HDAC5 (shHDAC5). After training rats to self-administer Meth, we tested the rats for relapse on withdrawal days 2 and 30. We also measured gene expression of other HDACs and potential HDAC5 downstream targets. Results We found that HDAC5 overexpression in dorsal striatum increased Meth seeking on withdrawal day 30 but not day 2. In contrast, HDAC5 knockdown in dorsal striatum decreased Meth seeking on withdrawal day 30 but not day 2; this manipulation also altered other HDACs (Hdac1 and Hdac4) and potential HDAC5 targets (Gnb4 and Suv39h1). Conclusions Results demonstrate a novel role of dorsal striatal HDAC5 in incubation of Meth craving. These findings also set up future work to identify HDAC5 targets that mediate this incubation.
Role of striatal direct pathway 2-arachidonoylglycerol signaling in sociability and repetitive behavior Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-28 Brian C. Shonesy, Walker P. Parrish, Hala K. Haddad, Jason R. Stephenson, Rita Báldi, Rebecca J. Bluett, Christian R. Marks, Samuel W. Centanni, Oakleigh M. Folkes, Keeley Spiess, Shana M. Augustin, Ken Mackie, David M. Lovinger, Danny G. Winder, Sachin Patel, Roger J. Colbran
Background Endocannabinoid signaling plays an important role in regulating synaptic transmission in the striatum, a brain region implicated as a central node of dysfunction in autism spectrum disorder (ASD). Deficits in signaling mediated by the endocannabinoid 2-arachidonoyl glycerol (2-AG) have been reported in mouse models of ASD, but a causal role for striatal 2-AG deficiency in ASD-relevant phenotypes has not been explored. Methods Using conditional knockout mice, we examined the electrophysiological, biochemical and behavioral effect of 2-AG deficiency by deleting its primary synthetic enzyme, diacylglycerol lipase alpha (DGLα) from D1-dopamine or A2a-adenosine receptor expressing medium spiny neurons (MSNs) to determine the role of 2-AG signaling in striatal direct or indirect pathways respectively. We then used viral-mediated deletion of DGLα to study the effects of 2-AG deficiency in ventral and dorsal striatum. Results Targeted deletion of DGLα from dMSNs caused deficits in social interaction, excessive grooming, and decreased exploration of a novel environment. In contrast, deletion from iMSNs had no effect on any measure of behavior examined. Loss of 2-AG in direct MSNs also led to increased glutamatergic drive, consistent with a loss of retrograde feedback-inhibition. Subregional DGLα deletion in dorsal striatum produced deficits in social interaction, whereas deletion from ventral striatum resulted in repetitive grooming. Conclusions These data suggest a role for 2-AG deficiency in social deficits and repetitive behavior, and demonstrate a key role for 2-AG in regulating striatal direct pathway MSNs.
Neural Mechanisms of Early-life Social Stress as a Developmental Risk Factor for Severe Psychiatric Disorders Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-28 Jonathan Rochus Reinwald, Robert Becker, Anne Stephanie Mallien, Claudia Falfan-Melgoza, Markus Sack, Christian Clemm von Hohenberg, Urs Braun, Alejandro Cosa Linan, Natalia Gass, Andrei-Nicolae Vasilescu, Fabian Tollens, Philipp Lebhardt, Natascha Pfeiffer, Dragos Inta, Andreas Meyer-Lindenberg, Peter Gass, Alexander Sartorius, Wolfgang Weber-Fahr
Background To explore the domain-general risk factor of early-life social stress in mental illness, rearing rodents in persistent post-weaning social isolation (PWSI) has been established as a widely-used animal model with translational relevance for neurodevelopmental psychiatric disorders like schizophrenia. Although changes in resting-state brain connectivity are a transdiagnostic key finding in neurodevelopmental diseases, a characterization of imaging correlates elicited by early-life social stress is lacking. Methods We performed resting-state functional Magnetic Resonance Imaging (rs-fMRI) of PWSI rats (N=23) nine weeks after isolation. Addressing well-established transdiagnostic connectivity changes of psychiatric disorders, we focused on altered frontal and posterior connectivity using a seed-based approach. Then, we examined changes in regional network architecture and global topology using graph theoretical analysis. Results Seed-based analyses demonstrated reduced functional connectivity (FC) in frontal and increased FC in posterior brain regions of PWSI rats. Graph analyses revealed a shift of the regional architecture, characterized by loss of dominance of frontal and emergence of non-frontal regions, correlating to our behavioral results, and a reduced modularity in isolation-reared rats. Conclusions Our result of FC alterations in the frontal brain support previous investigations postulating social neural circuits, including prefrontal brain regions, as key pathways for risk for mental disorders arising through social stressors. We extend this knowledge by demonstrating more wide-spread changes of brain network organization elicited by early-life social stress, namely a shift of hubness and dysmodularity. Our results highly resemble core alterations in neurodevelopmental psychiatric disorders like schizophrenia, autism and attention deficit hyperactivity disorder in humans.
Sodium Benzoate, a D-amino Acid Oxidase Inhibitor, Added to Clozapine for the Treatment of Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Trial Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-26 Chieh-Hsin Lin, Ching-Hua Lin, Yue-Cune Chang, Yu-Jhen Huang, Po-Wei Chen, Hui-Ting Yang, Hsien-Yuan Lane
Background Clozapine is the last-line antipsychotic agent for refractory schizophrenia. To date, there is no convincing evidence for augmentation on clozapine. Activation of NMDA receptors, including inhibition of D-amino acid oxidase (DAAO) that may metabolize D-amino acids, has been reported to be beneficial for patients receiving antipsychotics other than clozapine. This study aimed to examine the efficacy and safety of a DAAO inhibitor, sodium benzoate, for schizophrenia patients who had poor response to clozapine. Methods We conducted a randomized, double-blind, placebo-controlled trial. Sixty schizophrenia inpatients that had been stabilized with clozapine were allocated into three groups for six weeks add-on treatment of 1-g/d sodium benzoate, 2-g/d sodium benzoate, or placebo. The primary outcome measures were Positive and Negative Syndrome Scale (PANSS) total score, Scales for the Assessment of Negative symptoms (SANS), Quality of Life Scale (QOL), and Global Assessment of Function. Side-effect and cognitive functions were also measured. Results Both doses of sodium benzoate produced better improvement than placebo in SANS. 2-g/d sodium benzoate also produced better improvement than placebo in PANSS total score, PANSS-positive score, and QOL. Sodium benzoate was well tolerated without evident side-effects. The changes of catalase, an antioxidant, were different among the three groups and correlated with the improvement of PANSS total and PANSS-positive score in the sodium benzoate group. Conclusion Sodium benzoate adjuvant therapy improved symptomatology of patients with clozapine-resistant schizophrenia. Further studies are warranted to elucidate the optimal dose and treatment duration as well as the mechanisms of sodium benzoate for clozapine-resistant schizophrenia.
Metabolic and cardiovascular complications in obsessive-compulsive disorder: A total population, sibling comparison study with long-term follow-up Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-21 Kayoko Isomura, Gustaf Brander, Zheng Chang, Ralf Kuja-Halkola, Christian Rück, Clara Hellner, Paul Lichtenstein, Henrik Larsson, David Mataix-Cols, Lorena Fernández de la Cruz
Background Obsessive-compulsive disorder (OCD) is associated with increased mortality, but the causes of this increase are poorly understood. This study examined whether OCD is associated with an increased risk of metabolic and cardiovascular complications. Methods From a cohort of 12,497,002 individuals living in Sweden between 1973-2013, 25,415 individuals diagnosed with OCD were identified. Cox proportional hazard regression analyses investigated the risk of metabolic and cardiovascular complications in OCD patients, compared to the general population and to unaffected full siblings of OCD individuals. Exploratory analyses examined the effect of treatment with serotonin reuptake inhibitors (SRIs), with or without antipsychotics, on the outcomes of interest. Results Individuals with OCD had higher risk of any metabolic or cardiovascular complications, compared to the general population (hazard ratio [HR]=1.45; 95% CI=1.42–1.49) and their unaffected full siblings (HR=1.47; 95% CI=1.40–1.54). In the fully adjusted sibling comparison models, patients had higher risks of obesity, type 2 diabetes mellitus, and circulatory system diseases. The risks were already evident from the beginning of the follow-up and remained largely unchanged when excluding different groups of psychiatric comorbidities. Compared to patients not on SRIs, patients on higher doses of SRIs and longer duration of treatment had significantly lower risks of metabolic and cardiovascular complications, regardless of whether they were also on antipsychotics. Conclusions OCD is associated with an increased risk of metabolic and cardiovascular complications. Our results underscore the importance of carefully monitoring metabolic and cardiovascular health in patients with OCD early in the course of the disorder.
Gamma Ventral Capsulotomy in Intractable Obsessive-Compulsive Disorder Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-15 Steven A. Rasmussen, Georg Norén, Benjamin Greenberg, Richard Marsland, Nicole McLaughlin, Paul Malloy, Stephen Salloway, David Strong, Jane Eisen, Michael Jenike, Scott L. Rauch, Lee Baer, Christer Lindquist
Background In spite of the development of effective pharmacologic and cognitive behavioral treatments for obsessive-compulsive disorder (OCD), some patients continue to be treatment-refractory and severely impaired. Fiber tracts connecting orbitofrontal and dorsal anterior cingulate cortex with subcortical nuclei have been the target of neurosurgical lesions as well as deep brain stimulation in these patients. We report on the safety and efficacy of ventral gamma capsulotomy for patients with intractable OCD. Methods Fifty-five patients with severely disabling, treatment-refractory OCD received bilateral lesions in the ventral portion of the anterior limb of the internal capsule over a twenty-year period using the Leksell Gamma Knife. The patients were prospectively followed over three years with psychiatric, neurologic, and neuropsychological assessments of safety and efficacy, as well as structural neuroimaging. Results Thirty-one of fifty-five patients (56%) had an improvement in the primary efficacy measure, the Yale Brown Obsessive Compulsive Scale (YBOCS), of greater than or equal to 35% over the three year follow-up period. Patients had significant improvements in depression and anxiety as well as quality of life and global function. Patients tolerated the procedure well without significant acute adverse events. Five patients (9%) developed transient edema that required short courses of dexamethasone. Three patients (5%) developed cysts at long-term follow-up, one of whom developed radionecrosis resulting in an ongoing minimally conscious state. Conclusions Gamma knife ventral capsulotomy is an effective radiosurgical procedure for many treatment-refractory OCD patients. A minority of patients developed cysts at long-term follow-up, one of whom had permanent neurological sequelae. https://clinicaltrials.gov Safety and Effectiveness of Gamma Capsulotomy in Intractable OCD: NCT01849809
Impact of sleep and circadian rhythms on addiction vulnerability in adolescents Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-15 Ryan W. Logan, Brant P. Hasler, Erika E. Forbes, Peter L. Franzen, Mary M. Torregrossa, Yanhua H. Huang, Daniel J. Buysse, Duncan B. Clark, Colleen A. McClung
Sleep homeostasis and circadian function are important maintaining factors for optimal health and well-being. Conversely, sleep and circadian disruptions are implicated in a variety of adverse health outcomes including substance use disorders (SUDs). These risks are particularly salient during adolescence. Adolescents require 8-10 hours of sleep per night, although few consistently achieve these durations. A mismatch between developmental changes and social/environmental demands contributes to inadequate sleep. Homeostatic sleep drive takes longer to build, circadian rhythms naturally delay, and sensitivity to the phase-shifting effects of light increases, all of which lead to an evening preference (i.e., chronotype) during adolescence. On the other hand, school start times are often earlier and use of electronic devices at night increases, leading to disrupted sleep and circadian misalignment (i.e., social jet-lag). Social factors (e.g., peer influence) and school demands further impact sleep and circadian rhythms. To cope with sleepiness, many teens regularly consume highly caffeinated energy drinks and other stimulants, creating further disruptions in sleep. Chronic sleep loss and circadian misalignment enhance developmental tendencies towards increase reward sensitivity and impulsivity, increasing the likelihood of engaging in risky behaviors, and exacerbating the vulnerability to substance use and SUDs. We review the neurobiology of brain reward systems and the impact of sleep and circadian rhythms changes on addiction vulnerability in adolescence, and suggest areas that warrant further research.
Thalamic control of cognition and social behavior via regulation of GABAergic signaling and E/I balance in the medial prefrontal cortex Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-07 Brielle R. Ferguson, Wen-Jun Gao
Background The mediodorsal (MD) thalamus plays a critical role in cognition through its extensive innervation of the medial prefrontal cortex (mPFC), but how the two structures cooperate at the single-cell level to generate associated cognitive functions and other mPFC-dependent behaviors remains elusive. A principal importance for organizing cortical activity is maintaining the proper balance between excitation and inhibition (E/I balance). Further, the PFC E/I balance has been implicated in successful execution of multiple PFC-dependent behaviors in both animal research and the context of human psychiatric disorders. Methods Here, we utilized a pharmacogenetic strategy to decrease MD activity in adult male rats, and evaluated the consequences for E/I balance in PFC pyramidal neurons, as well as cognition, social interaction and anxiety. Results We found that dampening MD activity caused significant reductions in GABAergic signaling, increased E/I balance in the mPFC, and was concomitant with abnormalities in these behaviors. Further, by selectively activating parvalbumin (PV) interneurons in the mPFC with a novel pharmacogenetic approach, we restored GABAergic signaling and E/I balance, as well as ameliorated all behavioral impairments. Conclusions These findings underscore the importance of thalamocortical activation of mPFC GABAergic interneurons in a broad range of mPFC-dependent behaviors. Further, it highlights this circuitry as a platform for therapeutic investigation in psychiatric diseases that involve impairments in PFC-dependent behaviors.
Amphetamine Induced Striatal Dopamine Release Measured with an Agonist Radiotracer in Schizophrenia Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-07 W. Gordon Frankle, Jennifer Paris, Michael Himes, N. Scott Mason, Chester A. Mathis, Rajesh Narendran
Background Receptor imaging studies have reported increased amphetamine-induced dopamine release in subjects with schizophrenia relative to healthy controls. A limitation of these studies, performed with D2/3 antagonist radiotracers, is the failure to provide information about D2/3 receptors configured in a state of high affinity for the agonists (i.e., D2/3 receptors coupled to G-proteins, D2/3 HIGH). The endogenous agonist dopamine binds with preference to D2/3 HIGH relative to D2/3 LOW receptors making it critical to understand the status of D2/3 HIGH receptors in schizophrenia. Methods D2/3 agonist PET radiotracer [11C]NPA binding potential (BPND) was measured in 14 off medication subjects with schizophrenia (SCH) and 14 matched healthy controls (HC) at baseline and after the administration of 0.5 mg kg-1 oral d-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the post-amphetamine condition and BPND in the baseline condition, and expressed as a percentage of BPND at baseline. Results A trend-level increase was observed comparing baseline [11C]NPA BPND (RM ANOVA F=3.34, df=1,26, p=0.08) between SCH and HC. Amphetamine administration significantly decreased BPND in all striatal regions across all subjects in both groups. No differences were observed in [11C]NPA ΔBPND (RM ANOVA F=1.9, df=1,26, p=0.18) between HC and SCH. Amphetamine significantly increased positive symptoms in SCH subjects (19.5 ± 5.3 vs. 23.7 ± 4.1, paired T-test p < 0.0001) however no correlations were noted with [11C]NPA BPND or ΔBPND. Conclusions This study provides in vivo indication of a role for postsynaptic factors in amphetamine-induced psychosis in schizophrenia.
The emerging relationship between interstitial fluid-cerebrospinal fluid exchange, amyloid β and sleep Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-07 Erin L. Boespflug, Jeffrey J. Iliff
Amyloid β (Aβ) plaques are a key histopathological hallmark of Alzheimer’s disease (AD) and soluble Aβ species are believed to play an important role in the clinical development of this disease. Emerging biomarker data demonstrates that Aβ plaque deposition begins decades before the onset of clinical symptoms, suggesting that understanding the biological determinants of the earliest steps in the development of AD pathology may provide key opportunities for AD treatment and prevention. Although a clinical association between sleep disruption and AD has long been appreciated, emerging clinical studies and insights from the basic neurosciences has shed important new light on how sleep and Aβ homeostasis may be connected in the setting of AD. Aβ, like many interstitial solutes, is cleared in part through the exchange of brain interstitial fluid and cerebrospinal fluid (CSF) along a brain-wide network of perivascular pathways recently termed the ‘glymphatic’ system. Glymphatic function is primarily a feature of the sleeping, rather than the waking brain, and is slowed in the aging and post-traumatic brain. These changes may underlie the diurnal fluctuations in interstitial and CSF Aβ levels observed in both the rodent and human. These and other emerging studies suggest that age-related sleep disruption may be one key factor rendering the aging brain vulnerable to Aβ deposition and the development of AD. If true, sleep may represent a key modifiable risk factor or therapeutic target in the pre-clinical phases of AD.
Altered Gradients of Glutamate and GABA Transcripts in the Cortical Visuospatial Working Memory Network in Schizophrenia Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-07 Gil D. Hoftman, Samuel J. Dienel, Holly H. Bazmi, Yun Zhang, Kehui Chen, David A. Lewis
Background Visuospatial working memory (vsWM), which is impaired in schizophrenia, requires information transfer across multiple nodes in the cerebral cortex, including visual, posterior parietal, and dorsolateral prefrontal regions. Information is conveyed across these regions via the excitatory projections of glutamatergic pyramidal neurons located in layer 3, whose activity is modulated by local inhibitory GABAergic neurons. Key properties of these neurons differ across these cortical regions. Consequently, in schizophrenia, alterations in the expression of gene products regulating these properties could disrupt vsWM function in different ways, depending upon the region(s) affected. Methods Here, we quantified the expression of markers of glutamate and GABA neurotransmission selectively in layer 3 of four cortical regions in the vsWM network from 20 matched pairs of schizophrenia and unaffected comparison subjects. Results In comparison subjects, levels of glutamate transcripts tended to increase, whereas GABA transcript levels tended to decrease, from caudal-to-rostral across cortical regions of the vsWM network. Composite measures across all transcripts revealed a significant effect of region, with the glutamate measure lowest in primary visual cortex (V1) and highest in the dorsolateral prefrontal cortex (DLPFC), whereas the GABA measure showed the opposite pattern. In schizophrenia subjects, the expression levels of many of these transcripts were altered. However, this disease effect differed across regions such that the caudal-to-rostral increase in the glutamate measure was blunted and the caudal-to-rostral decline in the GABA measure was enhanced in the illness. Conclusions Differential alterations in layer 3 glutamate and GABA neurotransmission across cortical regions may contribute to vsWM deficits in schizophrenia.
CaMKII and eEF2K pathways mediate the antidepressant action of ketamine Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-05 Chinnakkaruppan Adaikkan, Elham Taha, Iliana Barrera, Orit David, Kobi Rosenblum
Background Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist, which upon administration, produces fast-acting anti-depressant responses in patients with major depressive disorder. Yet, the mechanism underlying the anti-depressant action of ketamine remains unclear. Methods To unravel the mechanism of action of ketamine, we treated wild type C57BL/6 with CaMKII specific inhibitor TatCN21 peptide. We also used eEF2-kinase (also known as CaMKIII) knockout mice. We analyzed the effects biochemically and behaviorally, using the forced swim, tail suspension, and novelty suppressed feeding tests. Results Consistent with the literature, here we report that one of the major pathways mediating the anti-depressant action of ketamine is reduction of phosphorylation of eEF2 via eEF2-kinase. Specifically, we show that knocking out eEF2K in mice eliminates phosphorylation of eEF2 at Thr-56, resulting in increased protein synthesis, and makes mice resistant both biochemically and behaviorally to the anti-depressant effects of ketamine. In addition, administration of ketamine leads to differential regulation of CaMKII function, manifested as auto-inhibition (pT305 phosphorylation) followed by auto-activation (pT286) of CaMKIIα in the hippocampus and cortex. The Inhibition phase of CaMKII, which lasts 10-20 min after administration of ketamine, occurs concurrently with eEF2K-dependent increased protein synthesis. Moreover, ketamine administration dependent delayed induction of GluA1 (24h) is regulated by the activation of CaMKII. Importantly, systemic administration of CaMKII inhibitor, TatCN21, increases global protein synthesis and induces behavioral resistance to ketamine. Conclusion Our data suggest that drugs which selectively target calcium-calmodulin dependent kinases and regulate protein-synthesis offer novel strategies for the treatment of major depressive disorder.
E2F3a in nucleus accumbens affects cocaine action via transcription and alternative splicing Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-05 Hannah M. Cates, Elizabeth A. Heller, Casey K. Lardner, Immanuel Purushothaman, Catherine J. Peña, Deena M. Walker, Michael Cahill, Rachael L. Neve, Li Shen, Rosemary C. Bagot, Eric J. Nestler
Background Lasting changes in gene expression in brain reward regions, including nucleus accumbens (NAc), contribute to persistent functional changes in the addicted brain. We and others have demonstrated that altered expression of several candidate transcription factors in NAc regulates drug responses. A recent large-scale genome-wide study from our group predicted E2F3 as a prominent upstream regulator of cocaine-induced changes in gene expression and alternative splicing. Methods We studied the expression of two E2F3 isoforms – E2F3a and E2F3b – in mouse NAc after repeated cocaine administration, and assayed the effects of overexpression or depletion of E2F3 isoforms in NAc on cocaine behavioral responses. We then performed RNA-seq to investigate the effect of E2F3a overexpression in this region on gene expression and alternative splicing, performed qChIP at downstream targets in NAc following E2F3a overexpression or repeated cocaine exposure. Sample sizes vary between experiments and are noted in the text. Results We show that E2F3a, but not E2F3b, overexpression in mouse NAc regulates cocaine-induced locomotor and place conditioning behavior. Furthermore, we demonstrate that E2F3a overexpression substantially recapitulates genome-wide transcriptional profiles and alternative splicing induced by cocaine. We further validate direct binding of E2F3a at key target genes following cocaine exposure. Conclusions This study establishes E2F3a as a novel transcriptional regulator of cocaine action in NAc. The findings reveal a crucial role for E2F3a in the regulation of cocaine-elicited behavioral states. Moreover, the importance of this role is bolstered by the extensive recapitulation of cocaine’s transcriptional effects in NAc upon expression of E2F3a.
Identification of a cortico-habenular circuit regulating socially-directed behavior Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-02 Madhurima Benekareddy, Tevye Jason Stachniak, Andreas Bruns, Frederic Knoflach, Markus von Kienlin, Basil Künnecke, Anirvan Ghosh
Background The prefrontal cortex (PFC) has been implicated in the pathophysiology of social dysfunction, but the specific circuit partners mediating PFC function in health and disease are unclear. Methods The excitatory DREADD hM3Dq was used to induce PFC activation during social behavior measured in the three-chamber sociability assay (rats/mice). fMRI was combined with hM3Dq-mediated PFC activation to identify novel nodes in the ‘social brain’ in a hypothesis-free manner. In multiplexed DREADD experiments, hM3Dq and the inhibitory KORDi were used to bidirectionally modulate PFC activity and measure social behavior and global fMRI signature. To characterize the functional role of specific nodes identified in this fMRI screen, we used anterograde and retrograde tracers, optogenetic and DREADD-assisted circuit mapping, and circuit behavioral experiments. Results PFC activation suppresses social behavior and modulates activity in a number of regions involved in emotional behavior. Bidirectional modulation of PFC activity further refined this subset of brain regions and identified the habenula as a node robustly correlated with PFC activity. Furthermore, we show that the lateral habenula (LHb) receives direct synaptic input from the PFC, and that activation of LHb neurons or the PFC inputs to the LHb suppresses social preference. Finally, we demonstrate that LHb inhibition can prevent the social deficits induced by PFC activation. Conclusion The LHb is thought to provide reward-related contextual information to the mesolimbic reward system known to be involved in social behavior. Thus, PFC projections to the LHb may represent an important part of descending PFC pathways that control social behavior.
Nuclear-Excluded Autism-Associated PTEN Mutations Dysregulate Neuronal Growth Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-02 Catherine J. Fricano-Kugler, Stephanie A. Getz, Michael R. Williams, Ashley A. Zurawel, Tyrone DeSpenza Jr., Paul W. Frazel, Meijie Li, Alistair J. O’Malley, Erika L. Moen, Bryan W. Luikart
Background Phosphatase and tensin homolog (PTEN) negatively regulates downstream AKT signaling resulting in decreased cellular growth and proliferation. PTEN is mutated in a subset of children with autism spectrum disorder (ASD); however, the mechanism by which specific point mutations alter PTEN function is largely unknown. Here, we assess how ASD-associated single-nucleotide variations in PTEN (ASD-PTEN) affect function. Methods We use viral-mediated molecular substitution of human PTEN into Pten knockout mouse neurons and assess neuronal morphology to determine the functional impact of ASD-PTEN. We employ molecular cloning to examine how PTEN’s stability, subcellular localization, and catalytic activity impact neuronal growth. Results We identify a set of ASD-PTEN mutations displaying altered lipid phosphatase function and subcellular localization. We demonstrate that wild-type PTEN can rescue the neuronal hypertrophy, while PTEN H93R, F241S, D252G, W274L, N276S and D326N fail to rescue this hypertrophy. A subset of these mutations lacks nuclear localization prompting us to examine the role of nuclear PTEN in regulating neuronal growth. We find that nuclear PTEN alone is sufficient to regulate soma size. Further, forced localization of the D252G and W274L mutations into the nucleus partially restore regulation of soma size. Conclusions ASD-PTEN mutations display decreased stability, catalytic activity, and/or altered subcellular localization. Mutations lacking nuclear localization uncover a novel mechanism whereby lipid phosphatase activity in the nucleus can regulate mTOR signaling and neuronal growth.
A genetic investigation of sex bias in the prevalence of attention deficit hyperactivity disorder Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-02 Joanna Martin, Raymond K. Walters, Ditte Demontis, Manuel Mattheisen, S. Hong Lee, Elise Robinson, Isabell Brikell, Laura Ghirardi, Henrik Larsson, Paul Lichtenstein, Nicholas Eriksson, Thomas Werge, Preben Bo Mortensen, Marianne Giørtz Pedersen, Ole Mors, Merete Nordentoft, David M. Hougaard, Jonas Bybjerg-Grauholm, Naomi R. Wray, Barbara Franke, Stephen V. Faraone, Michael C. O’Donovan, Anita Thapar, Anders D. Børglum, Benjamin M. Neale
Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish population-register data (N=77,905 cases, N=1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that females with ADHD may be at especially high risk of certain comorbid developmental conditions (i.e. autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score (PRS) analysis did not support a higher burden of ADHD common risk variants in female cases (OR=1.02 [0.98-1.06], p=0.28). In contrast, epidemiological sibling analyses revealed that the siblings of females with ADHD are at higher familial risk of ADHD than siblings of affected males (OR=1.14, [95% CI: 1.11-1.18], p=1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.
Novel Small-Molecule Inhibitors of Protein Kinase C Epsilon Reduce Ethanol Consumption in Mice Biol. Psychiatry (IF 11.412) Pub Date : 2017-12-02 Angelo Blasio, Jingyi Wang, Dan Wang, Florence P. Varodayan, Matthew B. Pomrenze, Jacklyn Miller, Anna M. Lee, Thomas McMahon, Sandeep Gyawali, Hua-Yu Wang, Marisa Roberto, Stanton McHardy, Michael A. Pleiss, Robert O. Messing
Background Despite the high cost and widespread prevalence of alcohol use disorders, treatment options are limited, underscoring the need for new, effective medications. Previous results using protein kinase C epsilon (PKCε) knockout mice, RNA interference against PKCε, and peptide inhibitors of PKCε predict that small-molecule inhibitors of PKCε should reduce alcohol consumption in humans. Methods We designed a new class of PKCε inhibitors based on the Rho-associated protein kinase (ROCK) inhibitor Y-27632. In vitro kinase and binding assays were used to identify the most potent compounds. Their effects on ethanol-stimulated synaptic transmission; ethanol, sucrose, and quinine consumption; ethanol-induced loss of righting; and ethanol clearance were studied in mice. Results We identified two compounds that inhibited PKCε with Ki <20 nM, showed selectivity for PKCε over other kinases, crossed the blood-brain barrier, achieved effective concentrations in mouse brain, prevented ethanol-stimulated gamma-aminobutyric acid release in the central amygdala, and reduced ethanol consumption when administered intraperitoneally at 40 mg/kg in wild-type but not in Prkce−/− mice. One compound also reduced sucrose and saccharin consumption, while the other was selective for ethanol. Both transiently impaired locomotion through an off-target effect that did not interfere with their ability to reduce ethanol intake. One compound prolonged recovery from ethanol-induced loss of righting but this was also due to an off-target effect since it was present in Prkce−/− mice. Neither altered ethanol clearance. Conclusions These results identify lead compounds for development of PKCε inhibitors that reduce alcohol consumption.
Prion protein as a toxic acceptor of amyloid-β oligomers Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-21 Silvia A. Purro, Andrew J. Nicoll, John Collinge
The initial report that cellular prion protein (PrPC) mediates toxicity of Amyloid-β (Aβ) species linked to Alzheimer’s disease was initially treated with scepticism, but growing evidence supports this claim. That there is a high-affinity interaction is now clear and its molecular basis is being unravelled whilst recent studies have identified possible down-stream toxic mechanisms. Determination of the clinical significance of such interactions between PrPC and disease-associated Aβ species will require experimental medicine studies in humans. Compounds that inhibit PrP-dependent Aβ toxicity are starting to be trialled in humans and, although it is clear that only a fraction of Alzheimer’s disease toxicity could be governed by PrPC, a partial but still therapeutically useful role in human disease may soon be testable.
Metabotropic Glutamate Receptor 2/3 as Targets for Treating Nicotine Addiction Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-21 Alan Cross, Robert Anthenelli, Xia Li
Tobacco smoking, driven by the addictive properties of nicotine, continues to be a worldwide health problem. Based on the well-established role of glutamatergic neurotransmission in drug addiction, novel medication development strategies seek to halt nicotine consumption and prevent relapse to tobacco smoking by modulating glutamate transmission. The presynaptic inhibitory metabotropic glutamate receptors (mGluR) 2/3 are key autoreceptors on glutamatergic terminals that maintain glutamate homeostasis. Accumulating evidence suggests the critical role of mGluR2/3 in different aspects of nicotine addiction, including acquisition and maintenance of nicotine taking, nicotine withdrawal, and persistent nicotine seeking even after prolonged abstinence. The involvement of mGluR2/3 in other neuropsychiatric diseases, such as anxiety, depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease and pain, provides convincing evidence suggesting that mGluR2/3 may provide an effective therapeutic approach for comorbidity of smoking and these disorders. This focused review article highlights that mGluR2/3 provide a promising target in the search for smoking cessation medication with novel mechanisms of actions that differ from those of currently FDA-approved pharmacotherapies.
Mechanisms of Sex Differences in Fear and PTSD Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-21 Teniel Sonya Ramikie, Kerry James Ressler
Following sexual maturity, females disproportionately have higher rates of post-traumatic stress disorder (PTSD) and experience greater symptom severity and chronicity as compared to males. This observation has led many to examine sex differences in PTSD risk factors. Though relatively few, these studies reveal that the root causes of PTSD sex differences are complex, and partly represent interactions between sex-specific non-biological and biological risk factors, which differentially shape PTSD vulnerability. Moreover, these studies suggest that sex-specific PTSD vulnerability is partly regulated by sex differences in fear systems. Fear, which represents a highly conserved adaptive response to threatening environmental stimuli, becomes pathological in trauma- and stress-based psychiatric syndromes, such as PTSD. Over the last 30 years, considerable progress has been made in understanding normal and pathological molecular and behavioral fear processes in humans and animal models. Thus, fear mechanisms represent a tractable PTSD biomarker in the study of sex-differences in normal and pathological fear. In this review, we will discuss studies that examine biological and non-biological sex differences which contribute to normal and pathological fear behaviors in humans and animal models. This, we hope, will shed greater light on the potential mechanisms that contribute to increased PTSD vulnerability in females.
The candidate schizophrenia risk gene DGCR2 regulates early steps of corticogenesis Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-21 Aude Molinard-Chenu, Alexandre Dayer
Background Alterations in early steps of cortical circuit assembly are thought to play a critical role in vulnerability to schizophrenia (SZ), but the pathogenic impact of SZ-risk mutations on corticogenesis remains to be determined. DiGeorge Critical Region 2 (DGCR2) is located in the 22q11.2 locus, whose deletion is a major risk factor for SZ. Moreover, exome sequencing of individuals with idiopathic SZ identified a rare missense mutation in DGCR2, further suggesting that DGCR2 is involved in SZ. Methods Here we investigated the function of Dgcr2 and the pathogenic impact of the SZ-risk DGCR2 mutation in mouse corticogenesis using in utero electroporation targeted to projection neurons (PN). Results Dgcr2 knock down (KD) impaired radial locomotion and final translocation of PN, leading to persistent laminar positioning alterations. The DGCR2 missense SZ-risk mutation had a pathogenic impact on PN laminar allocation by reducing protein expression. Mechanistically, we identified DGCR2 as a novel member of the REELIN complex, regulating the phosphorylation of REELIN-dependent substrates and the expression of REELIN-dependent transcriptional targets. Conclusion Overall, this study provides biological evidence that the SZ-risk gene DGCR2 regulates critical steps of early corticogenesis possibly through a REELIN-dependent mechanism. Additionally, we found that the SZ-risk mutation in DGCR2 has a pathogenic impact on cortical formation by reducing protein expression level, suggesting a functional role for DGCR2 haplo-insufficiency in the 22q11.2 deletion syndrome.
Specificity in etiology of subtypes of bipolar disorder: Evidence from a Swedish population-based family study Biol. Psychiatry (IF 11.412) Pub Date : 2017-11-20 Jie Song, Ralf Kuja-Halkola, Arvid Sjölander, Sarah E. Bergen, Henrik Larsson, Mikael Landén, Paul Lichtenstein
Background Uncertainty remains whether bipolar I disorder (BDI) and bipolar II disorder (BDII) differ etiologically. We used a population-based family sample to examine the etiological boundaries between BDI and BDII, by assessing their familial aggregation/co-aggregation, and by assessing the co-aggregation between them and schizophrenia, depression, attention-deficit/hyperactivity disorder, eating disorders, autism spectrum disorders, substance use disorders, anxiety disorders and personality disorders. Methods By linking Swedish national registers, we established a population-based cohort (N=15,685,511) and identified relatives with different biological relationships. Odds ratios (ORs) were used to measure the relative risk of BDI and BDII in relatives of individuals diagnosed with BDI (N=4,309) and BDII (N=4,178). The heritability for BDI and BDII and the genetic correlation across psychiatric disorders were estimated by variance decomposition analysis. Results Compared with the general population, the OR of BDI was 17.0 (95% confidence interval (CI) 13.1-22.0) in first-degree relatives of BDI patients; higher than that of BDII patients (OR 9.8, 95% CI 7.7-12.5). The ORs of BDII were 13.6 (95% CI 10.2-18.2) in first-degree relatives of BDII patients and 9.8 (95% CI 7.7-12.4) in relatives of BDI patients. The heritabilities for BDI and BDII were estimated at 57% (95% CI 32%-79%) and 46% (95% CI 21%-67%), respectively, with a genetic correlation estimated as 0.78 (95 %CI 0.36-1.00). The familial co-aggregation of other psychiatric disorders, in particular schizophrenia, showed different patterns for BDI and BDII. Conclusions Our results suggest a distinction between BDI and BDII in etiology, partly due to genetic differences.
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