CTCF regulates anxiety and depression like behavior and maintenance of neuronal identity in the adult mouse brain

CCCTC-binding factor (CTCF) is a chromatin binding factor that binds to DNA sequence specific sites and, together with cohesin complex, establishes chromatin loops and regulates gene expression. CTCF was previously implicated as a major contributor in neural development. Genetic aberrations in CTCF are associated with intellectual disability, aggression, attention deficit, and autistic behavior. Previous mice-model studies have identified a necessary role for CTCF during development of CaMKIIa expressing excitatory neurons in the ability of learning and memory. However, it is not clear if CTCF is only necessary for development in the brain, or also in maintenance of neuronal functions and behavior in the adulthood. In the current study, adulthood-specific knockout of CTCF in excitatory neurons induced an elevation in anxiety and depression related behavior and a decrease in seeking social novelty. Depression and apathy-like behavior was reversed by treatment with serotonin specific reuptake inhibitor sertraline. Golgi staining analysis reveals major regression of dendritic complexity in the hippocampus and prefrontal cortex. In parallel, there is increased DNA compaction and decreased global H3K9 acetylation. Single nuclei RNA sequencing confirms a retreat in neuronal subtype identity in excitatory neurons after knockout. Gene ontology analysis display upregulation of genes that related regulation of cell population, neuronal development and neuronal differentiation and migration. These findings determine that CTCF is required for a propriate function of the mature excitatory neurons, independent of roles during development. Significance StatementThe gene CTCF is an important regulator of gene expression. Mutations in CTCF have been identified in individuals with a range of neurodevelopmental disorders, including intellectual disability and autism. However, it is unknown if CTCF is important only for neuronal development, or plays functional roles in the brain during adulthood. The current study finds that CTCF deletion during adulthood in excitatory neurons induces a behavioral phenotype that that includes increase in anxiety and depression-like behavior and changes in social behavior. In addition, CTCF depletion in adulthood affects the morphology, identity and gene expression of these specific types of neurons. Therefore, CTCF is not only important in brain development, but also in maintenance of proper neuronal function and behavior during adulthood.