Multiple studies in the last several years have highlighted its important role in neuronal development and acquisition of normal brain architecture. Tcf4 is a basic helixвЂ“loopвЂ“helix (bHLH) TF implicated in schizophrenia, autism and PittвЂ“Hopkins syndrome. To this end, we investigated transcription factor 4 (Tcf4) because of its persistent expression in the adult mammalian brain throughout the lifespan and noted association with both neurodevelopmental and psychiatric disorders.

However, beyond the IEG, very little is known about TFs and their role in regulating the structure or function of mature neurons in the adult brain. Focusing on the immediate early response genes (IEG), these studies show that the synaptic changes are communicated to the nucleus to trigger gene regulation that influence downstream processing for memory formation and consolidation, thereby establishing the significance of gene regulation in short- and long-term neuronal plasticity. Beyond the steady-state fate-maintenance role, a substantial body of work has also demonstrated the role of TF-mediated gene regulation in neuronal activity. Studies in invertebrates and vertebrates have shown the importance of continual expression of certain TF in fate maintenance of specific neuronal subtypes. However, many TFs continue to be expressed in mature neurons long after neuronal development and throughout the adult lifespan, although our knowledge about the functions of these TF in mature neurons remain sparse. These findings not only provide insights for the functional relevance of continual expression of a psychiatric disease-risk gene in the adult brain but also identify previously unappreciated gene networks underpinning mature neuronal regulation during the adult lifespan.ДЄ large body of literature informs us about the role of transcription factors (TFs) in neural specification and morphogenesis during brain development. The profound changes both in the structure and excitability of adult neurons upon acute loss of Tcf4 indicates that proactive regulation of membrane-related processes underlies the functional and structural integrity of adult neurons. Meta-analysis of the adult-deleted neuronal transcriptome from our study with the existing datasets of embryonic Tcf4 deficiencies revealed plasma membrane and ciliary genes to underlie Tcf4-mediated structure-function regulation specifically in adult neurons. Interestingly, transcriptomic analysis of genetically traced adult-deleted FACS-sorted Tcf4-knockout neurons revealed that Tcf4 targets in adult neurons are distinct from those in the embryonic brain. Acute loss of Tcf4 in adult excitatory neurons in vivo caused hyperexcitability and increased dendritic complexity of neurons, effects that were distinct from previously observed effects in embryonic-deficiency models. Given the importance of Tcf4 in psychiatric diseases, we investigated its role in adult neurons using cell-specific deletion and genetic tracing in adult animals. However, Tcf4 continues to be abundantly expressed in adult brain neurons where its functions remain unknown. The schizophrenia-risk gene Tcf4 has been widely studied in the context of brain development using mouse models of haploinsufficiency, in utero knockdown and embryonic deletion.

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