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Transcription factor 4 (TCF4 alias ITF2, E2-2) is a basic helix-loop-helix (bHLH) protein associated with Pitt-Hopkins syndrome, intellectual disability and schizophrenia. Here we show that TCF4-dependent transcription in cortical neurons, cultured from embryonic rats of both sexes, is induced by neuronal activity via soluble adenylyl cyclase and protein kinase A (PKA) signalling. PKA directly phosphorylates TCF4 and a PKA phosphorylation site in TCF4 is necessary for its transcriptional activity in cultured neurons as well as in the developing brain in vivo We also demonstrate that Gadd45g (growth arrest and DNA damage inducible gamma) is a direct target of neuronal activity-induced TCF4-dependent transcriptional regulation and TCF4 missense variations identified in schizophrenia patients alter the transcriptional activity of TCF4 in neurons. Altogether, this study identifies a new role for TCF4 as a neuronal activity-regulated transcription factor, offering a novel perspective on the association of TCF4 with cognitive disorders.SIGNIFICANCE STATEMENTThe importance of the basic helix-loop-helix transcription factor TCF4 in the nervous system is underlined by its association with common and rare cognitive disorders. In the current study we show that TCF4-controlled transcription in primary cortical neurons is induced by neuronal activity and protein kinase A. Our results support the hypotheses that dysregulation of neuronal activity-dependent signalling plays a significant part in the aetiology of neuropsychiatric and neurodevelopmental disorders.

The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A