Role of schizophrenia-associated transcription factor Tcf4 in mature neurons

Abstract

The dendritic arbor of neurons is responsible for its circuit integration and is thought to be a largely stable structure in the adult brain, as opposed to the highly dynamic spines of the dendritic branches. However, alterations of neuronal dendritic structure have been noted during aging, stress, neurodegenerative, and psychiatric diseases, although the role of these changes, whether adaptive or detrimental, remains elusive. Tcf4, a transcription factor linked to neurodevelopmental and psychiatric disorders, plays a crucial role in brain development, and continues to be expressed in the adult brain. Haplo-insufficiency of Tcf4 leads to Pitt-Hopkins syndrome (PTHS), and mutations in the Tcf4 locus are associated with schizophrenia and autism spectrum disorders. Given the lack of understanding of Tcf4’s function in the adult brain, we investigated its function in projection neurons in adult mice. We discovered that Tcf4 is involved in maintaining the dendritic structure and membrane characteristics of mature neurons in the adult brain. Interestingly, we found that to maintain the structure and function of adult neurons, Tcf4 represses a broad network of genes, including those associated with cilia. We used the Tcf4-deletion model to further investigate the potential role of dendritic flexibility in adult neurons. Our findings show that CA1 projection neurons undergo adaptive dendritic rearrangements in response to alteration in the dendritic structure of their neighboring neurons. These findings offer insights into neuronal homeostatic maintenance and adaptability in the adult brain.