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Psychiatric risk gene Transcription Factor 4 (TCF4) regulates the density and connectivity of distinct inhibitory interneuron subtypes

Molecular Psychiatry volume 28, pages 4679–4692 (2023)Cite this article

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Abstract

Transcription factor 4 (TCF4) is a basic helix-loop-helix transcription factor that is implicated in a variety of psychiatric disorders including autism spectrum disorder (ASD), major depression, and schizophrenia. Autosomal dominant mutations in TCF4 are causal for a specific ASD called Pitt-Hopkins Syndrome (PTHS). However, our understanding of etiological and pathophysiological mechanisms downstream of TCF4 mutations is incomplete. Single cell sequencing indicates TCF4 is highly expressed in GABAergic interneurons (INs). Here, we performed cell-type specific expression analysis (CSEA) and cellular deconvolution (CD) on bulk RNA sequencing data from 5 different PTHS mouse models. Using CSEA we observed differentially expressed genes (DEGs) were enriched in parvalbumin expressing (PV+) INs and CD predicted a reduction in the PV+ INs population. Therefore, we investigated the role of TCF4 in regulating the development and function of INs in the Tcf4+/tr mouse model of PTHS. In Tcf4+/tr mice, immunohistochemical (IHC) analysis of subtype-specific IN markers and reporter mice identified reductions in PV+, vasoactive intestinal peptide (VIP+), and cortistatin (CST+) expressing INs in the cortex and cholinergic (ChAT+) INs in the striatum, with the somatostatin (SST+) IN population being spared. The reduction of these specific IN populations led to cell-type specific alterations in the balance of excitatory and inhibitory inputs onto PV+ and VIP+ INs and excitatory pyramidal neurons within the cortex. These data indicate TCF4 is a critical regulator of the development of specific subsets of INs and highlight the inhibitory network as an important source of pathophysiology in PTHS.

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Fig. 1: Cell type-specific expression analyses and cellular deconvolution of bulk RNA-seq data predicts a reduction in PV + INs in Tcf4+/mut mice.
Fig. 2: Dysregulation of IN specific gene expression in the PTHS mouse model.
Fig. 3: Reduced density of specific subclasses of INs in the PTHS mouse cortex.
Fig. 4: Reduced density of specific subclasses of INs in subcortical brain regions.
Fig. 5: Intrinsic and synaptic characteristics of PV + INs in the PTHS mouse model.
Fig. 6: Intrinsic and synaptic characteristics of VIP + INs in the medial prefrontal cortex of the PTHS mouse model.
Fig. 7: Excitatory and inhibitory synaptic characteristics of medial prefrontal pyramidal neurons in the PTHS mouse model.

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Data availability

Code for RNA-seq analyses in this study are available online at https://github.com/LieberInstitute/PTHS_interneurons. No new genomic sequencing experiments were performed in this study.

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Acknowledgements

We are grateful for the vision and generosity of the Lieber and Maltz families, who made this work possible. We thank Dr. Keri Martinowich for sharing the CST-cre and TdTom mouse lines. This work was supported by the Lieber Institute, the Pitt-Hopkins Research Foundation Award (BJM), and a NIMH grant R01MH110487 (BJM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, 21205, USA

    Huei-Ying Chen, Gina Shim, Gregory R. Hamersky, Norah Sadowski, Thomas S. O’Donnell, Srinidhi Rao Sripathy, Joseph F. Bohlen & Brady J. Maher

  2. Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, 15213, USA

    BaDoi N. Phan

  3. Neuroscience Institute, Carnegie Mellon University, Pittsburgh, PA, 15213, USA

    BaDoi N. Phan & Andreas R. Pfenning

  4. Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    BaDoi N. Phan & Andreas R. Pfenning

  5. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Norah Sadowski & Brady J. Maher

  6. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Brady J. Maher

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Contributions

H-YC and GS performed IHC and confocal imaging; H-YC, GS, TSO, SRS and JFB performed image analysis. H-YC and GRH performed electrophysiology experiments; H-YC and SRS performed qPCR and analysis. BNP performed RNA sequencing and ChIP-seq analysis under ARP supervision. NS performed RNA sequencing analysis on E13.5 samples. H-YC, GS and JFB performed mouse genotyping and colony maintenance. H-YC and BJM contributed to experimental design, data analyses and writing. All authors discussed the results and edited the manuscript.

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Correspondence to Brady J. Maher.

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Chen, HY., Phan, B.N., Shim, G. et al. Psychiatric risk gene Transcription Factor 4 (TCF4) regulates the density and connectivity of distinct inhibitory interneuron subtypes. Mol Psychiatry 28, 4679–4692 (2023). https://doi.org/10.1038/s41380-023-02248-z

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