Alterations of social interaction through genetic and environmental manipulation of the 22q11.2 gene Sept5 in the mouse brain

• Published in: Human molecular genetics 2012-08, Vol.21 (15), p.3489-3499
• Main Authors: HARPER, Kathryn M, HIRAMOTO, Takeshi, TANIGAKI, Kenji, KANG, Gina, SUZUKI, Go, TRIMBLE, William, HIROI, Noboru
• Format: Article
• Language: English
• Subjects: Amygdala; Animals; Anxiety - genetics; Behavior, Animal; Biological and medical sciences; Brain - metabolism; Chromosomes, Human, Pair 22 - genetics; Exploratory Behavior - physiology; Fundamental and applied biological sciences. Psychology; Gene-Environment Interaction; Genetics of eukaryotes. Biological and molecular evolution; Hippocampus; Humans; Male; Mice; Mice, Congenic; Mice, Inbred C57BL; Mice, Knockout; Molecular and cellular biology; Motor Activity; Phenotype; Schizophrenia - genetics; Septins - genetics; Social Behavior
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/dds180

Social behavior dysfunction is a symptomatic element of schizophrenia and autism spectrum disorder (ASD). Although altered activities in numerous brain regions are associated with defective social cognition and perception, the causative relationship between these altered activities and social cognition and perception-and their genetic underpinnings-are not known in humans. To address these issues, we took advantage of the link between hemizygous deletion of human chromosome 22q11.2 and high rates of social behavior dysfunction, schizophrenia and ASD. We genetically manipulated Sept5, a 22q11.2 gene, and evaluated its role in social interaction in mice. Sept5 deficiency, against a high degree of homogeneity in a congenic genetic background, selectively impaired active affiliative social interaction in mice. Conversely, virally guided overexpression of Sept5 in the hippocampus or, to a lesser extent, the amygdala elevated levels of active affiliative social interaction in C57BL/6J mice. Congenic knockout mice and mice overexpressing Sept5 in the hippocampus or amygdala were indistinguishable from control mice in novelty and olfactory responses, anxiety or motor activity. Moreover, post-weaning individual housing, an environmental condition designed to reduce stress in male mice, selectively raised levels of Sept5 protein in the amygdala and increased active affiliative social interaction in C57BL/6J mice. These findings identify this 22q11.2 gene in the hippocampus and amygdala as a determinant of social interaction and suggest that defective social interaction seen in 22q11.2-associated schizophrenia and ASD can be genetically and environmentally modified by altering this 22q11.2 gene.