Abstract
While the contributions of some genes to neuropsychiatric disorders are clear, the downstream neuronal effects are poorly understood. Over-expression of SHANK3, which encodes a key synaptic protein, causes neuropsychiatric phenotypes in humans and manic-like behavior in mice providing an opportunity to interrogate the role of SHANK3 in a subset of neurons that might underlie the manic-like behavior. Herein, we describe Shank3’s critical role in D2 dopamine receptor (D2dr) neurons and show that Shank3 overexpression causes increased synaptic neurotransmission in D2dr, but not D1dr, expressing striatal medium spiny neurons. Either pharmacologic D2dr inhibition or genetic normalization of Shank3 abundance in D2-neurons ameliorates manic-like behaviors. Integrating bioinformatic analyses of Shank3’s striatal interactome, D1 and D2 dopamine receptor binding proteins, and single-cell RNA-seq datasets, we demonstrate a functional relationship between Shank3 and the D2dr—but not the D1dr. Thus, while Shank3 is over-expressed in both D1 and D2 dopamine receptor expressing striatal neurons, D2 neuronal dysfunction causes manic-like behaviors.