Abstract
The mechanistic underpinnings of autism remain a subject of debate and controversy. Why do individuals with autism share an overlapping set of atypical behaviors and symptoms, despite having different genetic and environmental risk factors? A major challenge in developing new therapies for autism has been the inability to identify convergent neural phenotypes that could explain the common set of symptoms that result in the diagnosis. Although no striking macroscopic neuropathological changes have been identified in autism, there is growing evidence that inhibitory interneurons (INs) play an important role in its neural basis. In this Review, we evaluate and interpret this evidence, focusing on recent findings showing reduced density and activity of the parvalbumin class of INs. We discuss the need for additional studies that investigate how genes and the environment interact to change the developmental trajectory of INs, permanently altering their numbers, connectivity and circuit engagement.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lombardo, M. V., Lai, M. C. & Baron-Cohen, S. Big data approaches to decomposing heterogeneity across the autism spectrum. Mol. Psychiatry 24, 1435–1450 (2019).
Iakoucheva, L. M., Muotri, A. R. & Sebat, J. Getting to the cores of autism. Cell 178, 1287–1298 (2019).
Belmonte, M. K. et al. Autism and abnormal development of brain connectivity. J. Neurosci. 24, 9228–9231 (2004).
Hussman, J. P. Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism. J. Autism Dev. Disord. 31, 247–248 (2001).
Rubenstein, J. L. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).
Jeste, S. S. & Tuchman, R. Autism spectrum disorder and epilepsy: two sides of the same coin? J. Child Neurol. 30, 1963–1971 (2015).
Pan, P. Y., Bolte, S., Kaur, P., Jamil, S. & Jonsson, U. Neurological disorders in autism: a systematic review and meta-analysis. Autism 25, 812–830 (2021).
O’Donnell, C., Goncalves, J. T., Portera-Cailliau, C. & Sejnowski, T. J. Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders. Elife 6, e26724 (2017).
Marin, O. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci. 13, 107–120 (2012).
Ferguson, B. R. & Gao, W. J. PV Interneurons: critical regulators of E/I balance for prefrontal cortex-dependent behavior and psychiatric disorders. Front. Neural Circuits 12, 37 (2018).
Filice, F., Janickova, L., Henzi, T., Bilella, A. & Schwaller, B. The parvalbumin hypothesis of autism spectrum disorder. Front. Cell. Neurosci. 14, 577525 (2020).
Lunden, J. W., Durens, M., Phillips, A. W. & Nestor, M. W. Cortical interneuron function in autism spectrum condition. Pediatr. Res 85, 146–154 (2019).
Rossignol, E. Genetics and function of neocortical GABAergic interneurons in neurodevelopmental disorders. Neural Plast. 2011, 649325 (2011).
Hu, H., Gan, J. & Jonas, P. Interneurons. Fast-spiking, parvalbumin+ GABAergic interneurons: from cellular design to microcircuit function. Science 345, 1255263 (2014).
Gandal, M. J. et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359, 693–697 (2018).
Haney, J. R. et al. Broad transcriptomic dysregulation across the cerebral cortex in ASD. Preprint at BioRxiv https://doi.org/10.1101/2020.12.17.423129 (2020).
Williams, R. S., Hauser, S. L., Purpura, D. P., DeLong, G. R. & Swisher, C. N. Autism and mental retardation: neuropathologic studies performed in four retarded persons with autistic behavior. Arch. Neurol. 37, 749–753 (1980).
Markicevic, M. et al. Cortical excitation:inhibition imbalance causes abnormal brain network dynamics as observed in neurodevelopmental disorders. Cereb. Cortex 30, 4922–4937 (2020).
Casanova, M. F., Buxhoeveden, D. P., Switala, A. E. & Roy, E. Minicolumnar pathology in autism. Neurology 58, 428–432 (2002).
Wegiel, J. et al. The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol. 119, 755–770 (2010).
Varghese, M. et al. Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol. 134, 537–566 (2017).
Hutsler, J. J. & Zhang, H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 1309, 83–94 (2010).
Martinez-Cerdeño, V. Dendrite and spine modifications in autism and related neurodevelopmental disorders in patients and animal models. Dev. Neurobiol. 77, 393–404 (2017).
Fatemi, S. H., Reutiman, T. J., Folsom, T. D. & Thuras, P. D. GABAA receptor downregulation in brains of subjects with autism. J. Autism Dev. Disord. 39, 223–230 (2009).
Blatt, G. J. et al. Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J. Autism Dev. Disord. 31, 537–543 (2001).
Robertson, C. E., Ratai, E. M. & Kanwisher, N. Reduced GABAergic action in the autistic brain. Curr. Biol. 26, 80–85 (2016).
Horder, J. et al. GABAA receptor availability is not altered in adults with autism spectrum disorder or in mouse models. Sci. Transl. Med. 10, eaam8434 (2018).
Palmen, S. J., van Engeland, H., Hof, P. R. & Schmitz, C. Neuropathological findings in autism. Brain 127, 2572–2583 (2004).
Lawrence, Y. A., Kemper, T. L., Bauman, M. L. & Blatt, G. J. Parvalbumin-, calbindin-, and calretinin-immunoreactive hippocampal interneuron density in autism. Acta Neurol. Scand. 121, 99–108 (2010).
Hashemi, E., Ariza, J., Rogers, H., Noctor, S. C. & Martinez-Cerdeño, V. The number of parvalbumin-expressing interneurons is decreased in the prefrontal cortex in autism. Cereb. Cortex 27, 1931–1943 (2017).
Ariza, J., Rogers, H., Hashemi, E., Noctor, S. C. & Martinez-Cerdeño, V. The number of chandelier and basket cells are differentially decreased in prefrontal cortex in autism. Cereb. Cortex 28, 411–420 (2018).
Li, X. G., Somogyi, P., Tepper, J. M. & Buzsaki, G. Axonal and dendritic arborization of an intracellularly labeled chandelier cell in the CA1 region of rat hippocampus. Exp. Brain Res. 90, 519–525 (1992).
Gogolla, N. et al. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J. Neurodev. Disord. 1, 172–181 (2009).
Canetta, S. et al. Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons. Mol. Psychiatry 21, 956–968 (2016).
Godavarthi, S. K., Sharma, A. & Jana, N. R. Reversal of reduced parvalbumin neurons in hippocampus and amygdala of Angelman syndrome model mice by chronic treatment of fluoxetine. J. Neurochem. 130, 444–454 (2014).
Chen, Z. et al. Accumulated quiescent neural stem cells in adult hippocampus of the mouse model for the MECP2 duplication syndrome. Sci. Rep. 7, 41701 (2017).
Selby, L., Zhang, C. & Sun, Q. Q. Major defects in neocortical GABAergic inhibitory circuits in mice lacking the Fragile X mental retardation protein. Neurosci. Lett. 412, 227–232 (2007).
Wen, T. H. et al. Genetic reduction of matrix metalloproteinase-9 promotes formation of perineuronal nets around parvalbumin-expressing interneurons and normalizes auditory cortex responses in developing Fmr1 knock-out mice. Cereb. Cortex 28, 3951–3964 (2018).
Filice, F., Vorckel, K. J., Sungur, A. O., Wohr, M. & Schwaller, B. Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism. Mol. Brain 9, 10 (2016).
Lauber, E., Filice, F. & Schwaller, B. Dysregulation of parvalbumin expression in the Cntnap2−/− mouse model of autism spectrum disorder. Front Mol. Neurosci. 11, 262 (2018).
Penagarikano, O. et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235–246 (2011).
Hoffman, E. J. et al. Estrogens suppress a behavioral phenotype in zebrafish mutants of the autism risk gene, CNTNAP2. Neuron 89, 725–733 (2016).
Scott, R. et al. Loss of Cntnap2 causes axonal excitability deficits, developmental delay in cortical myelination, and abnormal stereotyped motor behavior. Cereb. Cortex 29, 586–597 (2019).
Smith, C. J. et al. Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number. Brain Behav. Immun. 90, 332–345 (2020).
Vogt, D., Cho, K. K. A., Lee, A. T., Sohal, V. S. & Rubenstein, J. L. R. The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles. Cell Rep. 11, 944–956 (2015).
Lim, L., Mi, D., Llorca, A. & Marin, O. Development and functional diversification of cortical interneurons. Neuron 100, 294–313 (2018).
Paluszkiewicz, S. M., Olmos-Serrano, J. L., Corbin, J. G. & Huntsman, M. M. Impaired inhibitory control of cortical synchronization in Fragile X syndrome. J. Neurophysiol. 106, 2264–2272 (2011).
Wong, F. K. et al. Pyramidal cell regulation of interneuron survival sculpts cortical networks. Nature 557, 668–673 (2018).
Southwell, D. G. et al. Intrinsically determined cell death of developing cortical interneurons. Nature 491, 109–113 (2012).
Wong, F. K. & Marin, O. Developmental cell death in the cerebral cortex. Annu. Rev. Cell Dev. Biol. 35, 523–542 (2019).
Denaxa, M. et al. Modulation of apoptosis controls inhibitory interneuron number in the cortex. Cell Rep. 22, 1710–1721 (2018).
Khazipov, R. et al. Early motor activity drives spindle bursts in the developing somatosensory cortex. Nature 432, 758–761 (2004).
Golshani, P. et al. Internally mediated developmental desynchronization of neocortical network activity. J. Neurosci. 29, 10890–10899 (2009).
Duan, Z. R. S. et al. GABAergic restriction of network dynamics regulates interneuron survival in the developing cortex. Neuron 105, 75–92 (2020).
del Rio, J. A., de Lecea, L., Ferrer, I. & Soriano, E. The development of parvalbumin-immunoreactivity in the neocortex of the mouse. Brain Res. Dev. Brain Res. 81, 247–259 (1994).
Priya, R. et al. Activity regulates cell death within cortical interneurons through a calcineurin-dependent mechanism. Cell Rep. 22, 1695–1709 (2018).
Marin, O. Developmental timing and critical windows for the treatment of psychiatric disorders. Nat. Med. 22, 1229–1238 (2016).
Nomura, T. et al. Delayed maturation of fast-spiking interneurons is rectified by activation of the TrkB receptor in the mouse model of Fragile X syndrome. J. Neurosci. 37, 11298–11310 (2017).
Petilla Interneuron Nomenclature Group, et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9, 557–568 (2008).
de Wit, J. & Ghosh, A. Specification of synaptic connectivity by cell surface interactions. Nat. Rev. Neurosci. 17, 22–35 (2016).
Polepalli, J. S. et al. Modulation of excitation on parvalbumin interneurons by neuroligin-3 regulates the hippocampal network. Nat. Neurosci. 20, 219–229 (2017).
Favuzzi, E. & Rico, B. Molecular diversity underlying cortical excitatory and inhibitory synapse development. Curr. Opin. Neurobiol. 53, 8–15 (2018).
Favuzzi, E. et al. Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits. Science 363, 413–417 (2019).
Fazzari, P. et al. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 464, 1376–1380 (2010).
Exposito-Alonso, D. et al. Subcellular sorting of neuregulins controls the assembly of excitatory-inhibitory cortical circuits. Elife 9, e57000 (2020).
de la Torre-Ubieta, L., Won, H., Stein, J. L. & Geschwind, D. H. Advancing the understanding of autism disease mechanisms through genetics. Nat. Med. 22, 345–361 (2016).
Polioudakis, D. et al. A single-cell transcriptomic atlas of human neocortical development during mid-gestation. Neuron 103, 785–801 (2019).
Velmeshev, D. et al. Single-cell genomics identifies cell type-specific molecular changes in autism. Science 364, 685–689 (2019).
Gandal, M. J. et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 362, eaat8127 (2018).
Helt, M. et al. Can children with autism recover? If so, how? Neuropsychol. Rev. 18, 339–366 (2008).
Shattuck, P. T. et al. Change in autism symptoms and maladaptive behaviors in adolescents and adults with an autism spectrum disorder. J. Autism Dev. Disord. 37, 1735–1747 (2007).
Gouwens, N. W. et al. Integrated morphoelectric and transcriptomic classification of cortical GABAergic cells. Cell 183, 935–953 (2020).
Krienen, F. M. et al. Innovations present in the primate interneuron repertoire. Nature 586, 262–269 (2020).
Tasic, B. et al. Adult mouse cortical cell taxonomy revealed by single-cell transcriptomics. Nat. Neurosci. 19, 335–346 (2016).
Lu, H. et al. Loss and gain of MeCP2 cause similar hippocampal circuit dysfunction that is rescued by deep brain stimulation in a Rett syndrome mouse model. Neuron 91, 739–747 (2016).
Goncalves, J. T., Anstey, J. E., Golshani, P. & Portera-Cailliau, C. Circuit-level defects in the developing neocortex of Fragile X mice. Nat. Neurosci. 16, 903–909 (2013).
La Fata, G. et al. FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry. Nat. Neurosci. 17, 1693–1700 (2014).
Cheyne, J. E., Zabouri, N., Baddeley, D. & Lohmann, C. Spontaneous activity patterns are altered in the developing visual cortex of the Fmr1 knockout mouse. Front. Neural Circuits 13, 57 (2019).
Zhang, N. et al. Decreased surface expression of the delta subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of Fragile X syndrome. Exp. Neurol. 297, 168–178 (2017).
El Idrissi, A. et al. Decreased GABAA receptor expression in the seizure-prone Fragile X mouse. Neurosci. Lett. 377, 141–146 (2005).
Tyzio, R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 343, 675–679 (2014).
He, Q., Nomura, T., Xu, J. & Contractor, A. The developmental switch in GABA polarity is delayed in Fragile X mice. J. Neurosci. 34, 446–450 (2014).
Contractor, A., Klyachko, V. A. & Portera-Cailliau, C. Altered neuronal and circuit excitability in Fragile X syndrome. Neuron 87, 699–715 (2015).
Zhang, Y. et al. Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice. Nat. Neurosci. 17, 1701–1709 (2014).
Rotschafer, S. & Razak, K. Altered auditory processing in a mouse model of Fragile X syndrome. Brain Res. 1506, 12–24 (2013).
Gibson, J. R., Bartley, A. F., Hays, S. A. & Huber, K. M. Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of Fragile X syndrome. J. Neurophysiol. 100, 2615–2626 (2008).
Chen, Q. et al. Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD. Nat. Neurosci. 23, 520–532 (2020).
Wallace, M. L., Burette, A. C., Weinberg, R. J. & Philpot, B. D. Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron-type-specific synaptic defects. Neuron 74, 793–800 (2012).
Robertson, C. E. & Baron-Cohen, S. Sensory perception in autism. Nat. Rev. Neurosci. 18, 671–684 (2017).
Antoine, M. W., Langberg, T., Schnepel, P. & Feldman, D. E. Increased excitation–inhibition ratio stabilizes synapse and circuit excitability in four autism mouse models. Neuron 101, 648–661 (2019).
Michaelson, S. D. et al. SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits. Nat. Neurosci. 21, 1–13 (2018).
Rolls, E. T. & Mills, W. P. C. Computations in the deep vs superficial layers of the cerebral cortex. Neurobiol. Learn. Mem. 145, 205–221 (2017).
He, C. X. et al. Tactile defensiveness and impaired adaptation of neuronal activity in the Fmr1 knock-out mouse model of autism. J. Neurosci. 37, 6475–6487 (2017).
Lovelace, J. W. et al. Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X syndrome. Neurobiol. Dis. 89, 126–135 (2016).
Green, S. A. et al. Neurobiology of sensory overresponsivity in youth with autism spectrum disorders. JAMA Psychiatry 72, 778–786 (2015).
Lee, S. H. et al. Activation of specific interneurons improves V1 feature selectivity and visual perception. Nature 488, 379–383 (2012).
Fu, Y. et al. A cortical circuit for gain control by behavioral state. Cell 156, 1139–1152 (2014).
Pi, H. J. et al. Cortical interneurons that specialize in disinhibitory control. Nature 503, 521–524 (2013).
Goel, A. et al. Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible. Nat. Neurosci. 21, 1404–1411 (2018).
Buzsaki, G. & Wang, X. J. Mechanisms of gamma oscillations. Annu. Rev. Neurosci. 35, 203–225 (2012).
Grice, S. J. et al. Disordered visual processing and oscillatory brain activity in autism and Williams syndrome. Neuroreport 12, 2697–2700 (2001).
Gandal, M. J. et al. Validating gamma oscillations and delayed auditory responses as translational biomarkers of autism. Biol. Psychiatry 68, 1100–1106 (2010).
Wilkinson, C. L., Levin, A. R., Gabard-Durnam, L. J., Tager-Flusberg, H. & Nelson, C. A. Reduced frontal gamma power at 24 months is associated with better expressive language in toddlers at risk for autism. Autism Res. 12, 1211–1224 (2019).
Ethridge, L. E. et al. Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in Fragile X syndrome. Mol. Autism 8, 22 (2017).
Cardin, J. A. et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459, 663–667 (2009).
Sohal, V. S., Zhang, F., Yizhar, O. & Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702 (2009).
Veit, J., Hakim, R., Jadi, M. P., Sejnowski, T. J. & Adesnik, H. Cortical gamma band synchronization through somatostatin interneurons. Nat. Neurosci. 20, 951–959 (2017).
Guyon, N. et al. Network asynchrony underlying increased broadband gamma power. J. Neurosci. 41, 2944–2963 (2021).
Lovelace, J. W., Ethell, I. M., Binder, D. K. & Razak, K. A. Translation-relevant EEG phenotypes in a mouse model of Fragile X syndrome. Neurobiol. Dis. 115, 39–48 (2018).
Kissinger, S. T. et al. Visual experience-dependent oscillations and underlying circuit connectivity changes are impaired in Fmr1 KO mice. Cell Rep. 31, 107486 (2020).
Pirbhoy, P. S. et al. Acute pharmacological inhibition of matrix metalloproteinase-9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice. J. Neurochem. 155, 538–558 (2020).
Radwan, B., Dvorak, D. & Fenton, A. A. Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice. Neurobiol. Dis. 88, 125–138 (2016).
Talbot, Z. N. et al. Normal CA1 place fields but discoordinated network discharge in a Fmr1-null mouse model of Fragile X syndrome. Neuron 97, 684–697 (2018).
Mukherjee, A., Carvalho, F., Eliez, S. & Caroni, P. Long-lasting rescue of network and cognitive dysfunction in a genetic schizophrenia model. Cell 178, 1387–1402 (2019).
Cheaha, D. & Kumarnsit, E. Alteration of spontaneous spectral powers and coherences of local field potential in prenatal valproic acid mouse model of autism. Acta Neurobiol. Exp. 75, 351–363 (2015).
Berzhanskaya, J., Phillips, M. A., Shen, J. & Colonnese, M. T. Sensory hypo-excitability in a rat model of fetal development in Fragile X syndrome. Sci. Rep. 6, 30769 (2016).
Marissal, T. et al. Restoring wild-type-like CA1 network dynamics and behavior during adulthood in a mouse model of schizophrenia. Nat. Neurosci. 21, 1412–1420 (2018).
Selimbeyoglu, A. et al. Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice. Sci. Transl. Med. 9, eaah6733 (2017).
Kozono, N., Okamura, A., Honda, S., Matsumoto, M. & Mihara, T. Gamma power abnormalities in a Fmr1-targeted transgenic rat model of Fragile X syndrome. Sci. Rep. 10, 18799 (2020).
Wohr, M. et al. Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Transl. Psychiatry 5, e525 (2015).
Deng, X., Gu, L., Sui, N., Guo, J. & Liang, J. Parvalbumin interneuron in the ventral hippocampus functions as a discriminator in social memory. Proc. Natl Acad. Sci. USA 116, 16583–16592 (2019).
Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011).
Andersen, J. et al. Generation of functional human 3D cortico-motor assembloids. Cell 183, 1913–1929 (2020).
Kang, Y. et al. A human forebrain organoid model of Fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies. Nat. Neurosci. 24, 1377–1391 (2021).
Donegan, J. J., Boley, A. M. & Lodge, D. J. Embryonic stem cell transplants as a therapeutic strategy in a rodent model of autism. Neuropsychopharmacology 43, 1789–1798 (2018).
Banerjee, A. et al. Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome. Proc. Natl Acad. Sci. USA 113, E7287–E7296 (2016).
Krishnan, K. et al. MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc. Natl Acad. Sci. USA 112, E4782–E4791 (2015).
Lazaro, M. T. et al. Reduced prefrontal synaptic connectivity and disturbed oscillatory population dynamics in the CNTNAP2 model of autism. Cell Rep. 27, 2567–2578 (2019).
Rotaru, D. C., van Woerden, G. M., Wallaard, I. & Elgersma, Y. Adult Ube3a gene reinstatement restores the electrophysiological deficits of prefrontal cortex layer 5 neurons in a mouse model of Angelman syndrome. J. Neurosci. 38, 8011–8030 (2018).
Mao, W. et al. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. Eur. J. Neurosci. 41, 1025–1035 (2015).
Berryer, M. H. et al. Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function. Nat. Commun. 7, 13340 (2016).
Codagnone, M. G. et al. Programming bugs: microbiota and the developmental origins of brain health and disease. Biol. Psychiatry 85, 150–163 (2019).
Buffington, S. A. et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775 (2016).
Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).
Azhari, A., Azizan, F. & Esposito, G. A systematic review of gut-immune-brain mechanisms in Autism Spectrum Disorder. Dev. Psychobiol. 61, 752–771 (2019).
Han, V. X. et al. Maternal acute and chronic inflammation in pregnancy is associated with common neurodevelopmental disorders: a systematic review. Transl. Psychiatry 11, 71 (2021).
Shi, L., Fatemi, S. H., Sidwell, R. W. & Patterson, P. H. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23, 297–302 (2003).
Shin Yim, Y. et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 549, 482–487 (2017).
Vasistha, N. A. et al. Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner. Mol. Psychiatry 25, 2313–2329 (2020).
Donato, F., Rompani, S. B. & Caroni, P. Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature 504, 272–276 (2013).
Dehorter, N. et al. Tuning of fast-spiking interneuron properties by an activity-dependent transcriptional switch. Science 349, 1216–1220 (2015).
Guo, J. & Anton, E. S. Decision making during interneuron migration in the developing cerebral cortex. Trends Cell Biol. 24, 342–351 (2014).
Oskvig, D. B., Elkahloun, A. G., Johnson, K. R., Phillips, T. M. & Herkenham, M. Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response. Brain Behav. Immun. 26, 623–634 (2012).
Su, P. et al. Disruption of SynGAP–dopamine D1 receptor complexes alters actin and microtubule dynamics and impairs GABAergic interneuron migration. Sci. Signal 12, eaau9122 (2019).
Ruden, J. B., Dugan, L. L. & Konradi, C. Parvalbumin interneuron vulnerability and brain disorders. Neuropsychopharmacology 46, 279–287 (2021).
Itami, C., Kimura, F. & Nakamura, S. Brain-derived neurotrophic factor regulates the maturation of layer 4 fast-spiking cells after the second postnatal week in the developing barrel cortex. J. Neurosci. 27, 2241–2252 (2007).
Hampson, D. R., Hooper, A. W. M. & Niibori, Y. The application of adeno-associated viral vector gene therapy to the treatment of Fragile X syndrome. Brain Sci. 9, 32 (2019).
Mossner, J. M., Batista-Brito, R., Pant, R. & Cardin, J. A. Developmental loss of MeCP2 from VIP interneurons impairs cortical function and behavior. Elife 9, e55639 (2020).
Lovelace, J. W. et al. Deletion of Fmr1 from forebrain excitatory neurons triggers abnormal cellular, EEG, and behavioral phenotypes in the auditory cortex of a mouse model of Fragile X syndrome. Cereb. Cortex 30, 969–988 (2020).
Acknowledgements
This review was inspired by the presentations of experts in the field during a three-day virtual conference entitled Interneurons Dysfunction in Autism held on 16–18 November 2020 (https://sites.google.com/view/interneurons-in-autism-2020/). The keynote speakers were J. Cardin, N. De Marco García, D. Feldman, A. Fenton, G. Fishell, M. Gandal, A. Goel, N. Gouwens, F. Krienen, V. M. Cerdeño, C. McBain and B. Rico. We are grateful to the speakers and all participants for their ideas. We also thank B. Rico, M. Gandal and C. McBain, as well as N. Kourdougli, A. Suresh, S. Sutley and M. Rais for their comments on this manuscript and help with the figures. This research is supported by grant 20160969 from The John Merck Fund to C.P.-C. and A.C., grants R01 HD054453 (National Institute of Child Health and Human Development (NICHD)/National Institutes of Health (NIH)) and R01 NS117597 (National Institute of Mental Health (NIMH)/NIH) and Simons Foundation Autism Research Initiative (SFARI) award no. 513155 to C.P.-C., grants R01 MH099114 (NIMH/NIH), R01 NS105502 (National Institute of Neurological Disorders and Stroke (NINDS)/NIH) and SFARI Pilot Award to A.C., grants W81XWH-17-1-0231 and WX81XWH-18-1-0777 from the US Army Medical Research and Materiel Command (Department of Defense) to A.C. and C.P.-C. and grant W81XWH-15-1-0436 from the Department of Defense to I.M.E.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information Nature Neuroscience thanks Elsa Rossignol and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Contractor, A., Ethell, I.M. & Portera-Cailliau, C. Cortical interneurons in autism. Nat Neurosci 24, 1648–1659 (2021). https://doi.org/10.1038/s41593-021-00967-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41593-021-00967-6
This article is cited by
-
Intersectional strategy to study cortical inhibitory parvalbumin-expressing interneurons
Scientific Reports (2024)
-
iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity
Nature Communications (2024)
-
Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
Nature (2023)
-
A genetics-first approach to understanding autism and schizophrenia spectrum disorders: the 22q11.2 deletion syndrome
Molecular Psychiatry (2023)
-
Non-standard diagnostic assessment reliability in psychiatry: a study in a Brazilian outpatient setting using Kappa
European Archives of Psychiatry and Clinical Neuroscience (2023)
