nArgBP2 regulates excitatory synapse formation by controlling dendritic spine morphology

Significance Recent studies have implicated postsynaptic scaffolding protein synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3) or Shank3 in mood disorders such as bipolar disorder, autism, and obsessive-compulsive disorders. Neural Abelson-related gene-binding protein 2 (nArgBP2) is a binding partner of both SAPAP3 and Shank3, and its genetic deletion in mice leads to manic/bipolar-like behavior resembling symptoms of bipolar disorder. Remarkably, nothing is known about the synaptic function of nArgBP2 or its connection with the synaptic alterations associated with bipolar disorder. Here, we provide compelling evidence that nArgBP2 regulates spine morphogenesis and that its ablation causes a robust and selective inhibition of excitatory synapse formation by controlling actin dynamics. Our results revealed the underlying mechanism for the synaptic dysfunction caused by nArgBP2 down-regulation that may be associated with human bipolar disorder.