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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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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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