Deficiency of Shank3 in the Nucleus Accumbens Reveals a Loss of Social-Specific Motivation

Deficits in social interaction are a hallmark symptom of autism and other neuropsychiatric disorders. SHANK3 encodes a postsynaptic density scaffold protein and is one of the most common causal genes for autism. SHANK3 protein is highly expressed in the nucleus accumbens (NAc), a critical brain region underlying motivated behavior, including social motivation. We previously reported that global Shank3 ^{Δe 4–22} deletion mice have decreased motivation for palatable food, increased unilateral social investigation, and show a hypoactive NAc and NAc-connected circuits. We thus developed a new Shank3 ^flox/flox mouse tool to conditionally knockdown SHANK3 in a region-specific manner. We found that knockdown of Shank3 in the NAc decreased social preference in the 3-chamber assay and decreased social motivation in the social conditioned place preference (sCPP) assay. Shank3- NAc deletion did not alter food reward seeking, reciprocal social investigation, or anxiety-like behaviors, that we report in global Shank3 ^{Δe 4–22} deletion mice. These data establish a novel and specific role of Shank3 in the NAc on social motivation.