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FXR1 regulation of parvalbumin interneurons in the prefrontal cortex is critical for schizophrenia-like behaviors

Molecular Psychiatry volume 26, pages 6845–6867 (2021)Cite this article

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Abstract

Parvalbumin interneurons (PVIs) are affected in many psychiatric disorders including schizophrenia (SCZ), however the mechanism remains unclear. FXR1, a high confident risk gene for SCZ, is indispensable but its role in the brain is largely unknown. We show that deleting FXR1 from PVIs of medial prefrontal cortex (mPFC) leads to reduced PVI excitability, impaired mPFC gamma oscillation, and SCZ-like behaviors. PVI-specific translational profiling reveals that FXR1 regulates the expression of Cacna1h/Cav3.2 a T-type calcium channel implicated in autism and epilepsy. Inhibition of Cav3.2 in PVIs of mPFC phenocopies whereas elevation of Cav3.2 in PVIs of mPFC rescues behavioral deficits resulted from FXR1 deficiency. Stimulation of PVIs using a gamma oscillation-enhancing light flicker rescues behavioral abnormalities caused by FXR1 deficiency in PVIs. This work unveils the function of a newly identified SCZ risk gene in SCZ-relevant neurons and identifies a therapeutic target and a potential noninvasive treatment for psychiatric disorders.

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Fig. 1: FXR1 deletion in PVIs leads to morphological defects of PVIs in the mPFC.
Fig. 2: FXR1 deletion in PVIs leads to impaired membrane excitability of PVIs and reduced gamma oscillation in the PFC.
Fig. 3: Selective knockdown of FXR1 in PVIs within the mPFC leads to schizophrenia-like behavioral deficits.
Fig. 4: FXR1 deficiency leads to reduced Cav3.2 levels in PVIs.
Fig. 5: Targeted manipulations of Cav3.2 in PVIs of mPFC directly impact behaviors.

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References

  1. Kessler RC, Aguilar-Gaxiola S, Alonso J, Chatterji S, Lee S, Ormel J, et al. The global burden of mental disorders: an update from the WHO World Mental Health (WMH) surveys. Epidemiol Psichiatr Soc. 2009;18:23–33.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60:1187–92.

    PubMed  Google Scholar 

  3. Niwa M, Cash-Padgett T, Kubo KI, Saito A, Ishii K, Sumitomo A, et al. DISC1 a key molecular lead in psychiatry and neurodevelopment: No-More Disrupted-in-Schizophrenia 1. Mol Psychiatry. 2016;21:1488–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Schizophrenia-Working-Group. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    Article  CAS  Google Scholar 

  5. Takata A, Matsumoto N, Kato T. Genome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci. Nat Commun. 2017;8:14519.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Liu X, Kelsoe JR, Greenwood TA. A genome-wide association study of bipolar disorder with comorbid eating disorder replicates the SOX2-OT region. J Affect Disord. 2016;189:141–9.

    Article  CAS  PubMed  Google Scholar 

  7. Pardinas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S, Carrera N, et al. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018;50:381–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Coelewij L, Curtis D. Mini-review: Update on the genetics of schizophrenia. Ann Hum Genet. 2018;82:239–43.

    Article  PubMed  Google Scholar 

  9. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018;362:eaat8127.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Rajarajan P, Borrman T, Liao W, Schrode N, Flaherty E, Casino C, et al. Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science. 2018;362:eaat4311.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Wang D, Liu S, Warrell J, Won H, Shi X, Navarro FCP, et al. Comprehensive functional genomic resource and integrative model for the human brain. Science. 2018;362:eaat8464.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Li M, Santpere G, Imamura Kawasawa Y, Evgrafov OV, Gulden FO, Pochareddy S, et al. Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science. 2018;362:eaat7615.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Siomi MC, Siomi H, Sauer WH, Srinivasan S, Nussbaum RL, Dreyfuss G. FXR1, an autosomal homolog of the fragile X mental retardation gene. Embo J. 1995;14:2401–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Li Y, Zhao X. Concise review: Fragile X proteins in stem cell maintenance and differentiation. Stem Cells. 2014;32:1724–33.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Patzlaff NE, Nemec KM, Malone SG, Li Y, Zhao X. Fragile X related protein 1 (FXR1P) regulates proliferation of adult neural stem cells. Hum Mol Genet. 2017;26:1340–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Cook D, Sanchez-Carbente Mdel R, Lachance C, Radzioch D, Tremblay S, Khandjian EW, et al. Fragile X related protein 1 clusters with ribosomes and messenger RNAs at a subset of dendritic spines in the mouse hippocampus. PLoS One. 2011;6:e26120.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Sakai Y, Shaw CA, Dawson BC, Dugas DV, Al-Mohtaseb Z, Hill DE, et al. Protein interactome reveals converging molecular pathways among autism disorders. Sci Transl Med. 2011;3:86ra49.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Zarnescu DC, Gregorio CC. Fragile hearts: new insights into translational control in cardiac muscle. Trends Cardiovasc Med. 2013;23:275–81.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Del’Guidice T, Latapy C, Rampino A, Khlghatyan J, Lemasson M, Gelao B, et al. FXR1P is a GSK3beta substrate regulating mood and emotion processing. Proc Natl Acad Sci USA. 2015;112:E4610–4619.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Khlghatyan J, Evstratova A, Chamberland S, Marakhovskaia A, Bahremand A, Toth K, et al. Mental illnesses-associated Fxr1 and its negative regulator Gsk3beta are modulators of anxiety and glutamatergic neurotransmission. Front Mol Neurosci. 2018;11:119.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Cook D, Nuro E, Jones EV, Altimimi HF, Farmer WT, Gandin V, et al. FXR1P limits long-term memory, long-lasting synaptic potentiation, and de novo GluA2 translation. Cell Rep. 2014;9:1402–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Cho RY, Konecky RO, Carter CS. Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci USA. 2006;103:19878–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry. 2015;77:1031–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Klausberger T, Somogyi P. Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science. 2008;321:53–57.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Isaacson JS, Scanziani M. How inhibition shapes cortical activity. Neuron. 2011;72:231–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Lee SH, Kwan AC, Dan Y. Interneuron subtypes and orientation tuning. Nature. 2014;508:E1–2.

    Article  CAS  PubMed  Google Scholar 

  28. Bartos M, Vida I, Jonas P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci. 2007;8:45–56.

    Article  CAS  PubMed  Google Scholar 

  29. Lewis DA, Hashimoto T, Volk DW. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci. 2005;6:312–24.

    Article  CAS  PubMed  Google Scholar 

  30. Bicks LK, Koike H, Akbarian S, Morishita H. Prefrontal cortex and social cognition in mouse and man. Front Psychol. 2015;6:1805.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Lisman J, Cooper K, Sehgal M, Silva AJ. Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability. Nat Neurosci. 2018;21:309–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Atallah BV, Bruns W, Carandini M, Scanziani M. Parvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli. Neuron. 2012;73:159–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Murray AJ, Woloszynowska-Fraser MU, Ansel-Bollepalli L, Cole KL, Foggetti A, Crouch B, et al. Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility. Sci Rep. 2015;5:16778.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Flaisher-Grinberg S, Einat H. A possible utilization of the mice forced swim test for modeling manic-like increase in vigor and goal-directed behavior. J Pharm Toxicol Methods. 2009;59:141–5.

    Article  CAS  Google Scholar 

  35. Mena A, Ruiz-Salas JC, Puentes A, Dorado I, Ruiz-Veguilla M, De la Casa LG. Reduced prepulse inhibition as a biomarker of schizophrenia. Front Behav Neurosci. 2016;10:202.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Hippenmeyer S, Vrieseling E, Sigrist M, Portmann T, Laengle C, Ladle DR, et al. A developmental switch in the response of DRG neurons to ETS transcription factor signaling. PLoS Biol. 2005;3:e159.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. Beckley JT, Woodward JJ. Volatile solvents as drugs of abuse: focus on the cortico-mesolimbic circuitry. Neuropsychopharmacology. 2013;38:2555–67.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Barker GR, Bird F, Alexander V, Warburton EC. Recognition memory for objects, place, and temporal order: a disconnection analysis of the role of the medial prefrontal cortex and perirhinal cortex. J Neurosci. 2007;27:2948–57.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Amodio DM, Frith CD. Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci. 2006;7:268–77.

    Article  CAS  PubMed  Google Scholar 

  40. Platt RJ, Chen S, Zhou Y, Yim MJ, Swiech L, Kempton HR, et al. CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell. 2014;159:440–55.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Reed MD, Yim YS, Wimmer RD, Kim H, Ryu C, Welch GM, et al. IL-17a promotes sociability in mouse models of neurodevelopmental disorders. Nature. 2020;577:249–53.

    Article  CAS  PubMed  Google Scholar 

  42. Burguiere E, Monteiro P, Feng G, Graybiel AM. Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science. 2013;340:1243–6.

    Article  CAS  PubMed  Google Scholar 

  43. Gao Y, Zhao X. sncRiboTag-Seq: cell-type-specific RiboTag-Seq for cells in low abundance in mouse brain tissue. STAR Protoc. 2021;2:100231.

    Article  PubMed  Google Scholar 

  44. Sanz E, Yang L, Su T, Morris DR, McKnight GS, Amieux PS. Cell-type-specific isolation of ribosome-associated mRNA from complex tissues. Proc Natl Acad Sci USA. 2009;106:13939–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Paul A, Crow M, Raudales R, He M, Gillis J, Huang ZJ. Transcriptional architecture of synaptic communication delineates GABAergic neuron identity. Cell. 2017;171:522–39 e520.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Patzlaff NE, Shen M, Zhao X. Regulation of adult neurogenesis by the fragile X family of RNA binding proteins. Brain Plast. 2018;3:205–23.

    Article  PubMed Central  PubMed  Google Scholar 

  47. Vasudevan S, Steitz JA. AU-rich-element-mediated upregulation of translation by FXR1 and Argonaute 2. Cell. 2007;128:1105–18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. He M, Liu Y, Wang X, Zhang MQ, Hannon GJ, Huang ZJ. Cell-type-based analysis of microRNA profiles in the mouse brain. Neuron. 2012;73:35–48.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Luo F, Tang H, Cheng ZY. Stimulation of alpha1-adrenoceptors facilitates GABAergic transmission onto pyramidal neurons in the medial prefrontal cortex. Neuroscience. 2015;300:63–74.

    Article  CAS  PubMed  Google Scholar 

  50. Wang G, Bochorishvili G, Chen Y, Salvati KA, Zhang P, Dubel SJ, et al. CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy. Genes Dev. 2015;29:1535–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Zhou H, Liu J, Zhou C, Gao N, Rao Z, Li H, et al. In vivo simultaneous transcriptional activation of multiple genes in the brain using CRISPR-dCas9-activator transgenic mice. Nat Neurosci. 2018;21:440–6.

    Article  CAS  PubMed  Google Scholar 

  52. Martorell AJ, Paulson AL, Suk HJ, Abdurrob F, Drummond GT, Guan W, et al. Multi-sensory gamma stimulation ameliorates Alzheimer’s-associated pathology and improves cognition. Cell. 2019;177:256–71.e222.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Bureau A, Beaulieu JM, Paccalet T, Chagnon YC, Maziade M. The interaction of GSK3B and FXR1 genotypes may influence the mania and depression dimensions in mood disorders. J Affect Disord. 2017;213:172–7.

    Article  CAS  PubMed  Google Scholar 

  54. Santos-Cortez RLP, Khan V, Khan FS, Mughal ZU, Chakchouk I, Lee K, et al. Novel candidate genes and variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability. Hum Genet. 2018;137:735–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Tran SS, Jun HI, Bahn JH, Azghadi A, Ramaswami G, Van Nostrand EL, et al. Widespread RNA editing dysregulation in brains from autistic individuals. Nat Neurosci. 2019;22:25–36.

    Article  CAS  PubMed  Google Scholar 

  56. Darnell JC, Fraser CE, Mostovetsky O, Darnell RB. Discrimination of common and unique RNA-binding activities among Fragile X mental retardation protein paralogs. Hum Mol Genet. 2009;18:3164–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Ascano M Jr, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature. 2012;492:382–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Cheever A, Ceman S. Translation regulation of mRNAs by the fragile X family of proteins through the microRNA pathway. RNA Biol. 2009;6:175–8.

    Article  CAS  PubMed  Google Scholar 

  59. Cheever A, Blackwell E, Ceman S. Fragile X protein family member FXR1P is regulated by microRNAs. Rna. 2010;16:1530–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Xu XL, Zong R, Li Z, Biswas MH, Fang Z, Nelson DL, et al. FXR1P but not FMRP regulates the levels of mammalian brain-specific microRNA-9 and microRNA-124. J Neurosci. 2011;31:13705–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell. 2011;146:247–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Boland MJ, Nazor KL, Tran HT, Szucs A, Lynch CL, Paredes R, et al. Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome. Brain. 2017;140:582–98.

    PubMed Central  PubMed  Google Scholar 

  63. Davidovic L, Durand N, Khalfallah O, Tabet R, Barbry P, Mari B, et al. A novel role for the RNA-binding protein FXR1P in myoblasts cell-cycle progression by modulating p21/Cdkn1a/Cip1/Waf1 mRNA stability. PLoS Genet. 2013;9:e1003367.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Zamponi GW, Striessnig J, Koschak A, Dolphin AC. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharm Rev. 2015;67:821–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Gangarossa G, Laffray S, Bourinet E, Valjent E. T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants. Front Behav Neurosci. 2014;8:92.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. Leresche N, Lambert RC. T-type calcium channels in synaptic plasticity. Channels. 2017;11:121–39.

    Article  PubMed  Google Scholar 

  67. Iaccarino HF, Singer AC, Martorell AJ, Rudenko A, Gao F, Gillingham TZ, et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature. 2016;540:230–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Yao Y, Zhang W, Ming R, Deng Q, Zuo A, Zhang S, et al. Noninvasive 40-Hz light flicker rescues circadian behavior and abnormal lipid metabolism induced by acute ethanol exposure via improving SIRT1 and the circadian clock in the liver-brain axis. Front Pharm. 2020;11:355.

    Article  CAS  Google Scholar 

  69. Xing F, Fang X, Gong XD, Zhao X, Du Y, Ma ZL, et al. Photoacoustic treatment mitigates cognitive dysfunction in a model of sleep-wake rhythm disturbance. Neural Regen Res. 2020;15:1094–101.

    Article  PubMed  Google Scholar 

  70. Zheng L, Yu M, Lin R, Wang Y, Zhuo Z, Cheng N, et al. Rhythmic light flicker rescues hippocampal low gamma and protects ischemic neurons by enhancing presynaptic plasticity. Nat Commun. 2020;11:3012.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Garza KM, Zhang L, Borron B, Wood LB, Singer AC. Gamma visual stimulation induces a neuroimmune signaling profile distinct from acute neuroinflammation. J Neurosci. 2020;40:1211–25.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Mientjes EJ, Willemsen R, Kirkpatrick LL, Nieuwenhuizen IM, Hoogeveen-Westerveld M, Verweij M, et al. Fxr1 knockout mice show a striated muscle phenotype: implications for Fxr1p function in vivo. Hum Mol Genet. 2004;13:1291–302.

    Article  CAS  PubMed  Google Scholar 

  73. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2010;13:133–40.

    Article  CAS  PubMed  Google Scholar 

  74. Shen M, Wang F, Li M, Sah N, Stockton ME, Tidei JJ, et al. Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice. Nat Neurosci. 2019;22:386–400.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  75. Gao Y, Shen M, Dong Q, Kannan S, Hoang J, Eisinger BE, et al. RGS6 mediates effects of voluntary running on adult hippocampal neurogenesis. Cell Rep. 2020;32:107997.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Franklin K, Paxinos G. The Mouse Brain in Stereotaxic Coordinates, Compact 3rd Edition. San Diego, CA: Elsevier Academic Press; 2008.

  77. Li Y, Stockton ME, Eisinger BE, Zhao Y, Miller JL, Bhuiyan I, et al. Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome. Nat Commun. 2018;9:2494.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  78. Swiech L, Heidenreich M, Banerjee A, Habib N, Li YQ, Trombetta J, et al. In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9. Nat Biotechnol. 2015;33:102–U286.

    Article  CAS  PubMed  Google Scholar 

  79. Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014;11:783–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  80. Dong Q, Liu Q, Li R, Wang A, Bu Q, Wang KH, et al. Mechanism and consequence of abnormal calcium homeostasis in Rett syndrome astrocytes. Elife. 2018;7:e33417.

    Article  PubMed Central  PubMed  Google Scholar 

  81. Sun QQ, Zhou C, Yang WG, Petrus D. Continuous spike-waves during slow-wave sleep in a mouse model of focal cortical dysplasia. Epilepsia. 2016;57:1581–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Franchi SA, Macco R, Astro V, Tonoli D, Savino E, Valtorta F, et al. A method to culture GABAergic interneurons derived from the medial ganglionic eminence. Front Cell Neurosci. 2017;11:423.

    Article  CAS  PubMed  Google Scholar 

  83. Li M, Shin J, Risgaard RD, Parries MJ, Wang J, Chasman D, et al. Identification of FMR1-regulated molecular networks in human neurodevelopment. Genome Res. 2020;30:361–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Jobe EM, Gao Y, Eisinger BE, Mladucky JK, Giuliani CC, Kelnhofer LE, et al. Methyl-CpG-binding protein MBD1 regulates neuronal lineage commitment through maintaining adult neural stem cell identity. J Neurosci. 2017;37:523–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  PubMed  Google Scholar 

  86. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    Article  CAS  PubMed  Google Scholar 

  87. Walf AA, Frye CA. The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc. 2007;2:322–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Deacon RM. Digging and marble burying in mice: simple methods for in vivo identification of biological impacts. Nat Protoc. 2006;1:122–4.

    Article  CAS  PubMed  Google Scholar 

  89. Allan AM, Liang X, Luo Y, Pak C, Li X, Szulwach KE, et al. The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits. Hum Mol Genet. 2008;17:2047–57.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Niu B, Liu P, Shen M, Liu C, Wang L, Wang F, et al. GRK5 regulates social behavior via suppression of mTORC1 signaling in medial prefrontal cortex. Cereb Cortex. 2018;28:421–32.

    Article  PubMed  Google Scholar 

  91. Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, et al. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature. 2007;446:41–45.

    Article  CAS  PubMed  Google Scholar 

  92. Alsene KM, Rajbhandari AK, Ramaker MJ, Bakshi VP. Discrete forebrain neuronal networks supporting noradrenergic regulation of sensorimotor gating. Neuropsychopharmacology. 2011;36:1003–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

We thank Y. Xing, S. Minemyer, R. Risgaard, R. Mishra, A. Stanko, P. Chugh, S. Pham, Y. Zhao, Y. Sun for technical assistance, V. Bakshi, B. Baldo and J. Panksepp for helping with PPI tests, S. Liu for helping with bioinformatics, J. Pinnow, M. Perez, M. Eastwood, D. Bolling, R. Emerson, H. Mitchell and K. Knobel at the Waisman IDD Model Core, S. Splinter-BonDurant and the UW-Madison Biotechnology Center for providing next generation sequencing services. This work was supported by grants from the National Institutes of Health (R01MH118827, R01NS105200, and R01MH116582 to XZ, R01HD064743 to QC, R01NS064025, R01AG067025, and U01MH116492 to DW, U54HD090256 to the Waisman Center; 5R01NS094550 and P20GM121310 to QS). Brain Research Foundation, UW Vilas (Mid-Career Award), Wisconsin Alumni Research Foundation, Jenni and Kyle Professorship (to XZ), and FRAXA Postdoctoral fellowship (to MS).

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Authors and Affiliations

  1. Waisman Center, University of Wisconsin-Madison, Madison, WI, USA

    Minjie Shen, Yu Guo, Qiping Dong, Yu Gao, Michael E. Stockton, Meng Li, Sudharsan Kannan, Tomer Korabelnikov, Keegan A. Schoeller, Carissa L. Sirois, Jonathan Le, Daifeng Wang, Qiang Chang & Xinyu Zhao

  2. Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

    Minjie Shen, Yu Guo, Yu Gao, Michael E. Stockton, Meng Li, Sudharsan Kannan, Tomer Korabelnikov, Keegan A. Schoeller, Carissa L. Sirois & Xinyu Zhao

  3. Department of Zoology and Physiology, University of Wyoming, Laramie, WY, USA

    Chen Zhou & Qian-Quan Sun

  4. Departments of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA

    Daifeng Wang

  5. Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, USA

    Qiang Chang

  6. Department of Neurology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

    Qiang Chang

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  16. Xinyu Zhao
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Contributions

XZ conceived the concept and designed experiments. MS designed and performed experiments, collected data, and analyzed data. MS and XZ wrote the manuscript. SK and CS performed bioinformatics analysis. MES, SK, TK. KAS and JL collected data. QD and QC performed electrophysiological analyses. CZ and QS performed iEEG recordings and analysis. DW performed gene expression analysis using PsychENCODE data.

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Correspondence to Xinyu Zhao.

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Shen, M., Guo, Y., Dong, Q. et al. FXR1 regulation of parvalbumin interneurons in the prefrontal cortex is critical for schizophrenia-like behaviors. Mol Psychiatry 26, 6845–6867 (2021). https://doi.org/10.1038/s41380-021-01096-z

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  • DOI: https://doi.org/10.1038/s41380-021-01096-z

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