CTCF in parvalbumin-expressing neurons regulates motor, anxiety and social behavior and neuronal identity

Abstract CCCTC-binding factor (CTCF) is a regulator of chromatin organization and has direct effects on gene transcription. Mutations in CTCF have been identified in individuals with neurodevelopmental conditions. There are wide range of behaviors associated with these mutations, including intellectual disabilities, changes in temperament, and autism. Previous mice-model studies have identified roles for CTCF in excitatory neurons in specific behaviors, particularly in regards to learning and memory. However, the role of CTCF in inhibitory neurons is less well defined. In the current study, specific knockout of CTCF in parvalbumin-expressing neurons, a subset of inhibitory neurons, induced a specific behavioral phenotype, including locomotor abnormalities, anxiolytic behavior, and a decrease in social behavior. The anxiolytic and social abnormalities are detected before the onset of locomotor abnormalities. Immunohistochemical analysis revealed a disbalance in parvalbumin-expressing and somatostatin-expressing cells in these mice. Single nuclei RNA sequencing identified changes in gene expression in parvalbumin-expressing neurons that are specific to inhibitory neuronal identity and function. Electrophysiology analysis revealed an enhanced inhibitory tone in the hippocampal pyramidal neurons in knockout mice. These findings indicate that CTCF in parvalbumin-expressing neurons has a significant role in the overall phenotype of CTCF-associated neurodevelopmental deficits.