Impaired vasopressin neuromodulation of the lateral septum leads to social behavior deficits in Shank3B+/- male mice

The neuropeptide arginine-vasopressin (AVP) has been repeatedly associated with the autism spectrum disorder (ASD) but the underlying mechanisms remain unclear. As Shank3B+/- male mice, a model of ASD, exhibit deficits in sociability and social aggression, we focused on the lateral septum (LS), a brain region involved in the regulation of motivated behaviors and observed reduced AVP inputs from the bed nucleus of the stria terminalis (BNST) to LS. Manipulating AVP release from the BNST to LS of wild-type male mice, we found that AVP promotes both sociability and social aggression. Blocking the vasopressin receptor 1a (AVPR1a) in LS impaired sociability, while blocking the receptor 1b (AVPR1b) disrupted social aggression. Consequently, selective activation of AVPR1a or AVPR1b rescued the respective behavioral deficits in Shank3B+/- male mice. These findings reveal that AVP release in LS modulates two distinct social behaviors via different receptors and highlight a possible strategy to rescue sociability during ASD.