Recent studies have strongly implicated postsynaptic scaffolding proteins such as SAPAP3 or Shank3 in the pathogenesis of various mood disorders including autism spectrum disorder, bipolar disorder (BD), and obsessive-compulsive disorders. Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that interacts with SAPAP3 and Shank3. Although recent study showed that genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behavior resembling symptoms of BD, the function of nArgBP2 at synapse or its connection with the synaptic dysfunctions is completely unknown. We provided compelling evidence that nArgBP2 regulates spine morphogenesis through the activation of Rac1/WAVE/PAK/cofilin pathway 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 downregulation that associates with analogous human BD. Moreover, since nArgBP2 interacts with key proteins involved in various neuropsychiatric disorders, our finding implies that nArgBP2 could function as a hub linking together etiological factors of different mood disorders.