Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression

27 Apr 2018

Psychiatric disorders are associated with aberrant brain development and/or aggressive behaviour, and are influenced by genetic factors; however, genes that affect brain aggression circuits remain elusive. Here we show that neuronal Src-homology-2 (SH2) B-adaptor protein-1 (Sh2b1) is indispensable for both brain growth and protection against aggression. Global and brain-specific deletion of Sh2b1 decreased brain weight and increased aggressive behaviour. Global and brain-specific Sh2b1 knockout mice exhibited fatal inter-male aggression. In a resident-intruder paradigm, latency to attack was markedly reduced, whereas the number and the duration of attacks was significantly increased in global and brain-specific Sh2b1 knockout mice compared to wild type littermates. Consistently, core aggression circuits were activated to a higher level in global and brain-specific Sh2b1 knockout males, based on c-fos immunoreactivity in the amygdala and periaqueductal grey. Brain-specific restoration of Sh2b1 normalized brain size and reversed pathological aggression and aberrant activation of core aggression circuits in Sh2b1 knockout males. SH2B1 mutations in humans were linked to aberrant brain development and behaviour. At the molecular level, Sh2b1 enhanced neurotrophin-stimulated neuronal differentiation, and protected against oxidative stress-induced neuronal death. Our data suggest that neuronal Sh2b1 promotes brain development and the integrity of core aggression circuits likely through enhancing neurotrophin signaling.