GluA3-deficiency in mice is associated with increased social and aggressive behavior and elevated dopamine in striatum

Glutamate signaling has been implicated in the regulation of social behavior. AMPA-glutamate receptors are assembled from four subunits (GluA1-4) of mainly GluA1/2 and GluA2/3 tetramers that form ion channels of distinct functional properties. Mice lacking GluA1 showed a reduced anxiety and male aggression. To understand the role of GluA3 in modulating social behavior, we investigated GluA3-deficient mice (Gria3-/Y) on C57BL/6J background. Compared to wild type (WT) littermates (n=14), Gria3-/Y mice (n=13) showed an increase in isolation-induced male aggression (p=0.011) in home cage resident-intruder test; an increase in sociability (p=0.01), and increase in male-male social interactions in neutral arena (p=0.005); an increase in peripheral activities in open field test (p=0.037) with normal anxiety levels in elevated plus maze and light-dark box; and minor deficits in motor and balance function in accelerating rotarod test (p=0.016) with normal grip strength. Gria3-/Y mice showed no significant deficit in spatial memory function in Morris-water maze and Y-maze tests, and normal levels of testosterone. Increased dopamine concentrations in stratum (p=0.034) and reduced serotonin turnover in olfactory bulb (p=0.002) were documented in Gria3-/Y mice. These results support a role of GluA3 in the modulation of social behavior through brain dopamine and/or serotonin signaling and different AMPA receptor subunits affect social behavior through distinct mechanisms.