FXR1 Regulation of Parvalbumin Interneurons in the Prefrontal Cortex is Critical for Schizophrenia-like Behaviors

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2021 Apr 17

PMID 33863995

Citations 19

Authors

Minjie Shen

Yu Guo

Qiping Dong

Yu Gao

Michael E Stockton

Meng Li

Sudharsan Kannan

Tomer Korabelnikov

Keegan A Schoeller

Carissa L Sirois

Chen Zhou

Jonathan Le

Daifeng Wang

Qiang Chang

Qian-Quan Sun

Xinyu Zhao

Affiliations

Soon will be listed here.

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.

Citing Articles

Fxr1 Deletion from Cortical Parvalbumin Interneurons Modifies Their Excitatory Synaptic Responses.

Scheuer K, Jansson A, Shen M, Zhao X, Jackson M eNeuro. 2025; 12(1).

PMID: 39753370 PMC: 11735682. DOI: 10.1523/ENEURO.0363-24.2024.

Fast-spiking parvalbumin-positive interneurons: new perspectives of treatment and future challenges in dementia.

Zhang X, Wu M, Cheng L, Cao W, Liu Z, Yang S Mol Psychiatry. 2024; 30(2):693-704.

PMID: 39695324 DOI: 10.1038/s41380-024-02756-6.

An in-depth review of the function of RNA-binding protein FXR1 in neurodevelopment.

Mendez-Albelo N, Sandoval S, Xu Z, Zhao X Cell Tissue Res. 2024; 398(2):63-77.

PMID: 39155323 DOI: 10.1007/s00441-024-03912-8.

The FXR1 network acts as a signaling scaffold for actomyosin remodeling.

Chen X, Fansler M, Janjos U, Ule J, Mayr C Cell. 2024; 187(18):5048-5063.e25.

PMID: 39106863 PMC: 11380585. DOI: 10.1016/j.cell.2024.07.015.

Pathogenesis, diagnosis, and treatment of epilepsy: electromagnetic stimulation-mediated neuromodulation therapy and new technologies.

Jiao D, Xu L, Gu Z, Yan H, Shen D, Gu X Neural Regen Res. 2024; 20(4):917-935.

PMID: 38989927 PMC: 11438347. DOI: 10.4103/NRR.NRR-D-23-01444.

References

Kessler R, Aguilar-Gaxiola S, Alonso J, Chatterji S, Lee S, Ormel J . The global burden of mental disorders: an update from the WHO World Mental Health (WMH) surveys. Epidemiol Psichiatr Soc. 2009; 18(1):23-33. PMC: 3039289. DOI: 10.1017/s1121189x00001421. View

Sullivan P, Kendler K, Neale M . Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003; 60(12):1187-92. DOI: 10.1001/archpsyc.60.12.1187. View

Niwa M, Cash-Padgett T, Kubo K, Saito A, Ishii K, Sumitomo A . DISC1 a key molecular lead in psychiatry and neurodevelopment: No-More Disrupted-in-Schizophrenia 1. Mol Psychiatry. 2016; 21(11):1488-1489. PMC: 5472474. DOI: 10.1038/mp.2016.154. View

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. PMC: 5333373. DOI: 10.1038/ncomms14519. View

Liu X, Kelsoe J, Greenwood T . A genome-wide association study of bipolar disorder with comorbid eating disorder replicates the SOX2-OT region. J Affect Disord. 2015; 189:141-9. PMC: 4640946. DOI: 10.1016/j.jad.2015.09.029. View

Pardinas A, Holmans P, Pocklington A, Escott-Price V, Ripke S, Carrera N . Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat Genet. 2018; 50(3):381-389. PMC: 5918692. DOI: 10.1038/s41588-018-0059-2. View

Coelewij L, Curtis D . Mini-review: Update on the genetics of schizophrenia. Ann Hum Genet. 2018; 82(5):239-243. DOI: 10.1111/ahg.12259. View

Gandal M, Zhang P, Hadjimichael E, Walker R, Chen C, Liu S . Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science. 2018; 362(6420). PMC: 6443102. DOI: 10.1126/science.aat8127. View

Rajarajan P, Borrman T, Liao W, Schrode N, Flaherty E, Casino C . Neuron-specific signatures in the chromosomal connectome associated with schizophrenia risk. Science. 2018; 362(6420). PMC: 6408958. DOI: 10.1126/science.aat4311. View

10.

Wang D, Liu S, Warrell J, Won H, Shi X, Navarro F . Comprehensive functional genomic resource and integrative model for the human brain. Science. 2018; 362(6420). PMC: 6413328. DOI: 10.1126/science.aat8464. View

11.

Li M, Santpere G, Kawasawa Y, Evgrafov O, Gulden F, Pochareddy S . Integrative functional genomic analysis of human brain development and neuropsychiatric risks. Science. 2018; 362(6420). PMC: 6413317. DOI: 10.1126/science.aat7615. View

12.

Siomi M, Siomi H, Sauer W, Srinivasan S, Nussbaum R, Dreyfuss G . FXR1, an autosomal homolog of the fragile X mental retardation gene. EMBO J. 1995; 14(11):2401-8. PMC: 398353. DOI: 10.1002/j.1460-2075.1995.tb07237.x. View

13.

Lek M, Karczewski K, Minikel E, Samocha K, Banks E, Fennell T . Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016; 536(7616):285-91. PMC: 5018207. DOI: 10.1038/nature19057. View

14.

Li Y, Zhao X . Concise review: Fragile X proteins in stem cell maintenance and differentiation. Stem Cells. 2014; 32(7):1724-33. PMC: 4255947. DOI: 10.1002/stem.1698. View

15.

Patzlaff N, Nemec K, Malone S, Li Y, Zhao X . Fragile X related protein 1 (FXR1P) regulates proliferation of adult neural stem cells. Hum Mol Genet. 2017; 26(7):1340-1352. PMC: 6075589. DOI: 10.1093/hmg/ddx034. View

16.

Cook D, Del Rayo Sanchez-Carbente M, Lachance C, Radzioch D, Tremblay S, Khandjian E . 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(10):e26120. PMC: 3191184. DOI: 10.1371/journal.pone.0026120. View

17.

Sakai Y, Shaw C, Dawson B, Dugas D, Al-Mohtaseb Z, Hill D . Protein interactome reveals converging molecular pathways among autism disorders. Sci Transl Med. 2011; 3(86):86ra49. PMC: 3169432. DOI: 10.1126/scitranslmed.3002166. View

18.

Zarnescu D, Gregorio C . Fragile hearts: new insights into translational control in cardiac muscle. Trends Cardiovasc Med. 2013; 23(8):275-81. PMC: 4142197. DOI: 10.1016/j.tcm.2013.03.003. View

19.

Delguidice T, Latapy C, Rampino A, Khlghatyan J, Lemasson M, Gelao B . FXR1P is a GSK3β substrate regulating mood and emotion processing. Proc Natl Acad Sci U S A. 2015; 112(33):E4610-9. PMC: 4547302. DOI: 10.1073/pnas.1506491112. View

20.

Khlghatyan J, Evstratova A, Chamberland S, Marakhovskaia A, Bahremand A, Toth K . Mental Illnesses-Associated Fxr1 and Its Negative Regulator Gsk3β Are Modulators of Anxiety and Glutamatergic Neurotransmission. Front Mol Neurosci. 2018; 11:119. PMC: 5906571. DOI: 10.3389/fnmol.2018.00119. View