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The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner

Molecular Psychiatry volume 23, pages 304–315 (2018)Cite this article

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Abstract

Disruption of the laminar and columnar organization of the brain is implicated in several psychiatric disorders. Here, we show in utero gain-of-function of the psychiatric risk gene transcription factor 4 (TCF4) severely disrupts the columnar organization of medial prefrontal cortex (mPFC) in a transcription- and activity-dependent manner. This morphological phenotype was rescued by co-expression of TCF4 plus calmodulin in a calcium-dependent manner and by dampening neuronal excitability through co-expression of an inwardly rectifying potassium channel (Kir2.1). For we believe the first time, we show that N-methyl-d-aspartate (NMDA) receptor-dependent Ca2+ transients are instructive to minicolumn organization because Crispr/Cas9-mediated mutation of NMDA receptors rescued TCF4-dependent morphological phenotypes. Furthermore, we demonstrate that the transcriptional regulation by the psychiatric risk gene TCF4 enhances NMDA receptor-dependent early network oscillations. Our novel findings indicate that TCF4-dependent transcription directs the proper formation of prefrontal cortical minicolumns by regulating the expression of genes involved in early spontaneous neuronal activity, and thus our results provides insights into potential pathophysiological mechanisms of TCF4-associated psychiatric disorders.

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Acknowledgements

We are grateful for the vision and generosity of the Lieber and Maltz families, who made this work possible. This work was supported by the Lieber Institute, NIH (R56MH104593), NIH (R01MH110487), NARSAD Young Investigator Award, and Pitt-Hopkins Research Foundation Award to BJM.

Author contributions

SCP contributed to all aspects of histological and calcium imaging experiments, data analysis and manuscript preparation. GRH and MDR performed electrophysiological experiments. GRH, RAG and MDR performed histological experiments. NEC performed co-IP experiments. RAG, MNC, BM and AB cloned and validated plasmid constructs. BNP and AEJ performed statistical analysis of calcium imaging experiments. BJM contributed to all aspects of experiments, electrophysiology, experimental design, writing and data analysis.

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Authors and Affiliations

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

    S C Page, G R Hamersky, R A Gallo, M D Rannals, N E Calcaterra, M N Campbell, B Mayfield, A Briley, B N Phan, A E Jaffe & B J Maher

  2. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    A E Jaffe

  3. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    A E Jaffe

  4. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA

    B J Maher

  5. Solomon H. Snyder Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA

    B J Maher

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  1. S C Page
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Correspondence to B J Maher.

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Page, S., Hamersky, G., Gallo, R. et al. The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner. Mol Psychiatry 23, 304–315 (2018). https://doi.org/10.1038/mp.2017.37

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