Social experience and sex-dependent regulation of aggression in the lateral septum by extrasynaptic δGABA A receptors

Rationale Understanding the neurobiological mechanisms mediating dominance and competitive aggression is essential to understanding the development and treatment of various psychiatric disorders. Previous research suggests that these mechanisms are both sexually differentiated and influenced substantially by social experience. In numerous species, GABA A receptors in the lateral septum have been shown to play a significant role in aggression in males. However, very little is known about the role of these GABA A receptors in female aggression, the role of social experience on GABA A receptor–mediated aggression, or the roles of different GABA A subtypes in regulating aggression. Objectives Thus, in the following set of experiments, we determined the role of social experience in modulating GABA A receptor–induced aggression in both male and female Syrian hamsters, with a particular focus on the GABA A receptor subtype mediating these effects. Results Activation of GABA A receptors in the dorsal lateral septum increased aggression in both males and females. Social housing, however, significantly decreased the ability of GABA A receptor activation to induce aggression in males but not females. No significant differences were observed in the effects of GABA A receptor activation in dominant versus subordinate group-housed hamsters. Finally, examination of potential GABA A receptor subtype specificity revealed that social housing decreased the ratio of δ extrasynaptic to γ 2 synaptic subunit GABA A receptor mRNA expression in the anterior dorsal lateral septum, while activation of δ extrasynaptic, but not γ 2 synaptic, GABA A receptors in the dorsal lateral septum increased aggression. Conclusions These data suggest that social experience can have profound effects on the neuronal mechanisms mediating aggression, especially in males, and that δ extrasynaptic GABA A receptors may be an important therapeutic target in disorders characterized by high levels of aggression.