Sept5: Alteration of social behavior through genetic and environmental manipulation of a 22q11.2 gene in mice

Abstract

Hemizygosity of human chromosome 22q11.2 is associated with aberrant social behavior and is a risk factor for autism and schizophrenia. Previously, an ∼200-kb region of 22q11.2 was found to be responsible for antipsychotic-responsive behaviors and defective prepulse inhibition in mice. I examined whether Septin 5 (Sept5), a gene in the ∼200 kb region, plays a role in the behavioral phenotype seen in 22q11.2 patients and if this phenotype is altered by genetic background and an environmental factor. First, I tested Sept5 knockout mice on a mixed genetic background, a genetic background enriched with 129X1/SvJ alleles, and a congenic background of C57BL/6J. Sept5 knock-out mice showed lower levels of social interaction, compared to wild-type mice, but this phenotype was influenced by genetic backgrounds. Other phenotypes in anxiety behavior, prepulse inhibition, and rewarded approach were variably influenced by genetic backgrounds. These data suggest that Sept5 deficiency exerts pleiotropic effects on a select set of behaviors and that genetic background could provide an epistatic influence on phenotypic expression. Second, I examined the impact of postnatal housing conditions on behavior and Sept5 levels in the brain. Male C57BL/6J mice were either individually-housed or group-housed at weaning until they were behaviorally tested or sacrificed to examine Sept5 levels at 9 weeks. Individually-housed mice exhibited more social interaction and motor activity, but lower levels of anxiety behaviors, compared to group-housed mice. Moreover, individual housing selectively increased Sept5 levels in the amygdala. These data suggest that a housing condition alters social interaction and Sept5 in the amygdala. Third, to assess the impact of Sept5 levels in the amygdala on social interaction, I over-expressed Sept5 in this region of male C57BL/6J mice using a lentiviral vector. Over-expression of Sept5 in the amygdala and areas dorsal to it increased social interaction. These data identify the amygdala and its dorsally adjacent regions as sites through which Sept5 alters social behavior. Given that defective social cognition is thought to underlie symptoms of autism and schizophrenia, these studies suggest that Sept5 contributes to 22q11.2-associated neuropsychiatric disorders.