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Layers II/III of Prefrontal Cortex in Df(h22q11)/+ Mouse Model of the 22q11.2 Deletion Display Loss of Parvalbumin Interneurons and Modulation of Neuronal Morphology and Excitability

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Abstract

The 22q11.2 deletion has been identified as a risk factor for multiple neurodevelopmental disorders. Behavioral and cognitive impairments are common among carriers of the 22q11.2 deletion. Parvalbumin expressing (PV+) interneurons provide perisomatic inhibition of excitatory neuronal circuits through GABAA receptors, and a deficit of PV+ inhibitory circuits may underlie a multitude of the behavioral and functional deficits in the 22q11.2 deletion syndrome. We investigated putative deficits of PV+ inhibitory circuits and the associated molecular, morphological, and functional alterations in the prefrontal cortex (PFC) of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. We detected a significant decrease in the number of PV+ interneurons in layers II/III of PFC in Df(h22q11)/+ mice together with a reduction in the mRNA and protein levels of GABAA (α3), a PV+ putative postsynaptic receptor subunit. Pyramidal neurons from the same layers further experienced morphological reorganizations of spines and dendrites. Accordingly, a decrease in the levels of the postsynaptic density protein 95 (PSD95) and a higher neuronal activity in response to the GABAA antagonist bicuculline were measured in these layers in PFC of Df(h22q11)/+ mice compared with their wild-type littermates. Our study shows that a hemizygotic deletion of the 22q11.2 locus leads to deficit in the GABAergic control of network activity and involves molecular and morphological changes in both the inhibitory and excitatory synapses of parvalbumin interneurons and pyramidal neurons specifically in layers II/III PFC.

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References

  1. Meechan DW, Maynard TM, Gopalakrishna D, Wu Y, LaMantia AS (2007) When half is not enough: gene expression and dosage in the 22q11 deletion syndrome. Gene Expr 13(6):299–310

    Article  CAS  Google Scholar 

  2. Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, Antaki D, Shetty A et al (2017) Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet 49(1):27–35. https://doi.org/10.1038/ng.3725

    Article  CAS  PubMed  Google Scholar 

  3. Niklasson L, Rasmussen P, Oskarsdottir S, Gillberg C (2009) Autism, ADHD, mental retardation and behavior problems in 100 individuals with 22q11 deletion syndrome. Res Dev Disabil 30(4):763–773. https://doi.org/10.1016/j.ridd.2008.10.007

    Article  PubMed  Google Scholar 

  4. Chow EW, Watson M, Young DA, Bassett AS (2006) Neurocognitive profile in 22q11 deletion syndrome and schizophrenia. Schizophr Res 87(1–3):270–278. https://doi.org/10.1016/j.schres.2006.04.007

    Article  PubMed  PubMed Central  Google Scholar 

  5. Woodin M, Wang PP, Aleman D, McDonald-McGinn D, Zackai E, Moss E (2001) Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genet Med 3(1):34–39. https://doi.org/10.1097/00125817-200101000-00008

    Article  CAS  PubMed  Google Scholar 

  6. Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P et al (2008) Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat Genet 40(6):751–760. https://doi.org/10.1038/ng.138

    Article  CAS  PubMed  Google Scholar 

  7. Paylor R, McIlwain KL, McAninch R, Nellis A, Yuva-Paylor LA, Baldini A, Lindsay EA (2001) Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments. Hum Mol Genet 10(23):2645–2650. https://doi.org/10.1093/hmg/10.23.2645

    Article  CAS  PubMed  Google Scholar 

  8. Sakurai T, Gamo NJ, Hikida T, Kim SH, Murai T, Tomoda T, Sawa A (2015) Converging models of schizophrenia--network alterations of prefrontal cortex underlying cognitive impairments. Prog Neurobiol 134:178–201. https://doi.org/10.1016/j.pneurobio.2015.09.010

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wood JN, Romero SG, Makale M, Grafman J (2003) Category-specific representations of social and nonsocial knowledge in the human prefrontal cortex. J Cogn Neurosci 15(2):236–248. https://doi.org/10.1162/089892903321208178

    Article  CAS  PubMed  Google Scholar 

  10. Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S, Belforte JE (2012) GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology 62(3):1574–1583. https://doi.org/10.1016/j.neuropharm.2011.01.022

    Article  CAS  Google Scholar 

  11. Yu Z, Fang Q, Xiao X, Wang YZ, Cai YQ, Cao H, Hu G, Chen Z et al (2013) GABA transporter-1 deficiency confers schizophrenia-like behavioral phenotypes. PLoS One 8(7):e69883. https://doi.org/10.1371/journal.pone.0069883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Freund TF, Katona I (2007) Perisomatic inhibition. Neuron 56(1):33–42. https://doi.org/10.1016/j.neuron.2007.09.012

    Article  CAS  PubMed  Google Scholar 

  13. Lagler M, Ozdemir AT, Lagoun S, Malagon-Vina H, Borhegyi Z, Hauer R, Jelem A, Klausberger T (2016) Divisions of identified parvalbumin-expressing basket cells during working memory-guided decision making. Neuron 91(6):1390–1401. https://doi.org/10.1016/j.neuron.2016.08.010

    Article  CAS  PubMed  Google Scholar 

  14. Cardin JA, Carlen M, Meletis K, Knoblich U, Zhang F, Deisseroth K, Tsai LH, Moore CI (2009) Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459(7247):663–667. https://doi.org/10.1038/nature08002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sohal VS, Zhang F, Yizhar O, Deisseroth K (2009) Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459(7247):698–702. https://doi.org/10.1038/nature07991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ferguson BR, Gao WJ (2018) PV interneurons: critical regulators of E/I balance for prefrontal cortex-dependent behavior and psychiatric disorders. Front Neural Circuits 12:37. https://doi.org/10.3389/fncir.2018.00037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Murray AJ, Woloszynowska-Fraser MU, Ansel-Bollepalli L, Cole KL, Foggetti A, Crouch B, Riedel G, Wulff P (2015) Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility. Sci Rep 5:16778. https://doi.org/10.1038/srep16778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. da Silva AF, Boot E, Schmitz N, Nederveen A, Vorstman J, Lavini C, Pouwels PJ, de Haan L et al (2011) Proton magnetic resonance spectroscopy in 22q11 deletion syndrome. PLoS One 6(6):e21685. https://doi.org/10.1371/journal.pone.0021685

    Article  CAS  Google Scholar 

  19. Philip N, Bassett A (2011) Cognitive, behavioural and psychiatric phenotype in 22q11.2 deletion syndrome. Behav Genet 41(3):403–412. https://doi.org/10.1007/s10519-011-9468-z

    Article  PubMed  PubMed Central  Google Scholar 

  20. Didriksen M, Fejgin K, Nilsson SR, Birknow MR, Grayton HM, Larsen PH, Lauridsen JB, Nielsen V et al (2017) Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice. J Psychiatry Neurosci 42(1):48–58. https://doi.org/10.1503/jpn.150381

    Article  PubMed  Google Scholar 

  21. Nilsson SRO, Heath CJ, Takillah S, Didienne S, Fejgin K, Nielsen V, Nielsen J, Saksida LM et al (2018) Continuous performance test impairment in a 22q11.2 microdeletion mouse model: Improvement by amphetamine. Transl Psychiatry 8:247. https://doi.org/10.1038/s41398-018-0295-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tripathi A, Spedding M, Schenker E, Didriksen M, Cressant A, Jay TM (2020) Cognition- and circuit-based dysfunction in a mouse model of 22q11.2 microdeletion syndrome: effects of stress. Transl Psychiatry 10(1):41. https://doi.org/10.1038/s41398-020-0687-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gundersen HJ (2002) The smooth fractionator. J Microsc 207(Pt 3):191–210. https://doi.org/10.1046/j.1365-2818.2002.01054.x

    Article  CAS  PubMed  Google Scholar 

  24. Van De Werd HJ, Uylings HB (2014) Comparison of (stereotactic) parcellations in mouse prefrontal cortex. Brain Struct Funct 219(2):433–459. https://doi.org/10.1007/s00429-013-0630-7

    Article  Google Scholar 

  25. Andersen CL, Jensen JL, Orntoft TF (2004) Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res 64(15):5245–5250. https://doi.org/10.1158/0008-5472.CAN-04-0496

    Article  CAS  PubMed  Google Scholar 

  26. Van De Werd HJJM, Rajkowska G, Evers P, Uylings HBM (2010) Cytoarchitectonic and chemoarchitectonic characterization of the prefrontal cortical areas in the mouse. Brain Struct Funct 214(4):339–353. https://doi.org/10.1007/s00429-010-0247-z

    Article  CAS  Google Scholar 

  27. Al-Absi AR, Christensen HS, Sanchez C, Nyengaard JR (2018) Evaluation of semi-automatic 3D reconstruction for studying geometry of dendritic spines. J Chem Neuroanat 94:119–124. https://doi.org/10.1016/j.jchemneu.2018.10.008

    Article  CAS  PubMed  Google Scholar 

  28. Paxinos G, Franklin KBJ, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San Diego

    Google Scholar 

  29. Yger P, Spampinato GL, Esposito E, Lefebvre B, Deny S, Gardella C, Stimberg M, Jetter F et al (2018) A spike sorting toolbox for up to thousands of electrodes validated with ground truth recordings in vitro and in vivo. Elife 7. https://doi.org/10.7554/eLife.34518

  30. Beneyto M, Abbott A, Hashimoto T, Lewis DA (2011) Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia. Cereb Cortex 21(5):999–1011. https://doi.org/10.1093/cercor/bhq169

    Article  PubMed  Google Scholar 

  31. Berggaard N, Seifi M, van der Want JJL, Swinny JD (2018) Spatiotemporal distribution of GABAA receptor subunits within layer II of mouse medial entorhinal cortex: implications for grid cell excitability. Front Neuroanat 12:46. https://doi.org/10.3389/fnana.2018.00046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lewis DA, Curley AA, Glausier JR, Volk DW (2012) Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 35(1):57–67. https://doi.org/10.1016/j.tins.2011.10.004

    Article  CAS  PubMed  Google Scholar 

  33. Chattopadhyaya B, Cristo GD (2012) GABAergic circuit dysfunctions in neurodevelopmental disorders. Front Psychiatry 3:51. https://doi.org/10.3389/fpsyt.2012.00051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lawrence YA, Kemper TL, Bauman ML, Blatt GJ (2010) Parvalbumin-, calbindin-, and calretinin-immunoreactive hippocampal interneuron density in autism. Acta Neurol Scand 121(2):99–108. https://doi.org/10.1111/j.1600-0404.2009.01234.x

    Article  CAS  PubMed  Google Scholar 

  35. Buzsaki G, Wang XJ (2012) Mechanisms of gamma oscillations. Annu Rev Neurosci 35:203–225. https://doi.org/10.1146/annurev-neuro-062111-150444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chattopadhyaya B, Di Cristo G, Wu CZ, Knott G, Kuhlman S, Fu Y, Palmiter RD, Huang ZJ (2007) GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex. Neuron 54(6):889–903. https://doi.org/10.1016/j.neuron.2007.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Larsen KM, Pellegrino G, Birknow MR, Kjaer TN, Baare WFC, Didriksen M, Olsen L, Werge T et al (2018) 22q11.2 deletion syndrome is associated with impaired auditory steady-state gamma response. Schizophr Bull 44(2):388–397. https://doi.org/10.1093/schbul/sbx058

    Article  PubMed  Google Scholar 

  38. Lewis DA, Cruz DA, Melchitzky DS, Pierri JN (2001) Lamina-specific deficits in parvalbumin-immunoreactive varicosities in the prefrontal cortex of subjects with schizophrenia: evidence for fewer projections from the thalamus. Am J Psychiatry 158(9):1411–1422. https://doi.org/10.1176/appi.ajp.158.9.1411

    Article  CAS  PubMed  Google Scholar 

  39. Hoftman GD, Datta D, Lewis DA (2017) Layer 3 excitatory and inhibitory circuitry in the prefrontal cortex: developmental trajectories and alterations in schizophrenia. Biol Psychiatry 81(10):862–873. https://doi.org/10.1016/j.biopsych.2016.05.022

    Article  PubMed  Google Scholar 

  40. Nathanson AJ, Davies PA, Moss SJ (2019) Inhibitory synapse formation at the axon initial segment. Front Mol Neurosci 12:266. https://doi.org/10.3389/fnmol.2019.0026641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lewis DA (2012) Cortical circuit dysfunction and cognitive deficits in schizophrenia—implications for preemptive interventions. Eur J Neurosci 35(12):1871–1878. https://doi.org/10.1111/j.1460-9568.2012.08156.x

    Article  PubMed  PubMed Central  Google Scholar 

  42. Loup F, Picard F, Andre VM, Kehrli P, Yonekawa Y, Wieser HG, Fritschy JM (2006) Altered expression of alpha3-containing GABAA receptors in the neocortex of patients with focal epilepsy. Brain 129(Pt 12):3277–3289. https://doi.org/10.1093/brain/awl287

    Article  PubMed  Google Scholar 

  43. Niturad CE, Lev D, Kalscheuer VM, Charzewska A, Schubert J, Lerman-Sagie T, Kroes HY, Oegema R et al (2017) Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. Brain 140(11):2879–2894. https://doi.org/10.1093/brain/awx236

    Article  PubMed  Google Scholar 

  44. Fiorelli R, Rudolph U, Straub CJ, Feldon J, Yee BK (2008) Affective and cognitive effects of global deletion of alpha 3-containing gamma-aminobutyric acid-A receptors. Behav Pharmacol 19(5–6):582–596. https://doi.org/10.1097/FBP.0b013e32830dc0c7

    Article  CAS  PubMed  Google Scholar 

  45. Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, Montrose D (2008) Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry 165(12):1585–1593. https://doi.org/10.1176/appi.ajp.2008.08030395

    Article  PubMed  PubMed Central  Google Scholar 

  46. Mukherjee A, Carvalho F, Eliez S, Caroni P (2019) Long-lasting rescue of network and cognitive dysfunction in a genetic schizophrenia model. Cell 178(6):1387–1402 e1314. https://doi.org/10.1016/j.cell.2019.07.023

    Article  CAS  PubMed  Google Scholar 

  47. Kimoto S, Muraki K, Toritsuka M, Mugikura S, Kajiwara K, Kishimoto T, Illingworth E, Tanigaki K (2012) Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome. Transl Psychiatry 2:e146. https://doi.org/10.1038/tp.2012.70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mohler H (2007) Molecular regulation of cognitive functions and developmental plasticity: impact of GABAA receptors. J Neurochem 102(1):1–12. https://doi.org/10.1111/j.1471-4159.2007.04454.x

    Article  CAS  PubMed  Google Scholar 

  49. Melchitzky DS, Sesack SR, Pucak ML, Lewis DA (1998) Synaptic targets of pyramidal neurons providing intrinsic horizontal connections in monkey prefrontal cortex. J Comp Neurol 390(2):211–224. https://doi.org/10.1002/(sici)1096-9861(19980112)390:2<211::aid-cne4>3.0.co;2-4

    Article  CAS  PubMed  Google Scholar 

  50. Sudhof TC, Malenka RC (2008) Understanding synapses: past, present, and future. Neuron 60(3):469–476. https://doi.org/10.1016/j.neuron.2008.10.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Glausier JR, Lewis DA (2013) Dendritic spine pathology in schizophrenia. Neuroscience 251:90–107. https://doi.org/10.1016/j.neuroscience.2012.04.044

    Article  CAS  PubMed  Google Scholar 

  52. Glantz LA, Lewis DA (2000) Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57(1):65–73. https://doi.org/10.1001/archpsyc.57.1.65

    Article  CAS  PubMed  Google Scholar 

  53. Coley AA, Gao WJ (2018) PSD95: a synaptic protein implicated in schizophrenia or autism? Prog Neuro-Psychopharmacol Biol Psychiatry 82:187–194. https://doi.org/10.1016/j.pnpbp.2017.11.016

    Article  CAS  Google Scholar 

  54. Mukai J, Tamura M, Fenelon K, Rosen AM, Spellman TJ, Kang R, MacDermott AB, Karayiorgou M et al (2015) Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia. Neuron 86(3):680–695. https://doi.org/10.1016/j.neuron.2015.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hu H, Gan J, Jonas P (2014) Interneurons. Fast-spiking, parvalbumin(+) GABAergic interneurons: from cellular design to microcircuit function. Science 345(6196):1255263. https://doi.org/10.1126/science.1255263

    Article  CAS  PubMed  Google Scholar 

  56. Marowsky A, Rudolph U, Fritschy JM, Arand M (2012) Tonic inhibition in principal cells of the amygdala: a central role for alpha 3 subunit-containing GABA(A) receptors. J Neurosci 32(25):8611–8619. https://doi.org/10.1523/Jneurosci.4404-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Helene M. Andersen and Jan Jacobsen for excellent technical assistance and Prof. Dr. Ulrich Egert (Bernstein Center Freiburg, Freiburg University) and Szilard Sajgo (Department of Biomedicine, Aarhus University) for their valuable assistance with the acquisition and the analysis of data from the HD-MEA.

Contributions

A.R.A. performed the experiments, A.R.A., P.Q., S.O., and A.R.K. analyzed and interpreted the results. The first draft of the manuscript was written by A.R.A. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This study was supported by the Department of Clinical Medicine at Aarhus University, Henny Sophie Clausen og møbelarkitekt Aksel Clausens Fond, and Centre for Stochastic Geometry, and the latter is supported by Villum Foundation (no specified grant number). The funders had no role in design of this study, analysis and interpretation of data, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Centre for Molecular Morphology, Section for Stereology and Microscopy; Centre for Stochastic Geometry and Advanced Bioimaging, Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard, 99 8200, Aarhus N, Denmark

    Abdel-Rahman Al-Absi & Jens R. Nyengaard

  2. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Per Qvist & Simon Glerup

  3. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark

    Per Qvist

  4. Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark

    Per Qvist

  5. Centre for Genomics and Personalized Medicine, CGPM, Aarhus University, Aarhus, Denmark

    Per Qvist

  6. Laboratory for Biomicrotechnology, Department of Microsystems Engineering IMTEK, University of Freiburg, Freiburg, Germany

    Samora Okujeni

  7. Center of Functionally Integrative Neuroscience (CFIN), Aarhus University, Aarhus, Denmark

    Ahmad Raza Khan

  8. Centre of Biomedical Research (CBMR), SGPGIMS Campus, Lucknow, India

    Ahmad Raza Khan

  9. Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark

    Connie Sanchez

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  1. Abdel-Rahman Al-Absi
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  7. Jens R. Nyengaard
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Correspondence to Abdel-Rahman Al-Absi.

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Al-Absi, AR., Qvist, P., Okujeni, S. et al. Layers II/III of Prefrontal Cortex in Df(h22q11)/+ Mouse Model of the 22q11.2 Deletion Display Loss of Parvalbumin Interneurons and Modulation of Neuronal Morphology and Excitability. Mol Neurobiol 57, 4978–4988 (2020). https://doi.org/10.1007/s12035-020-02067-1

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