Decrease of GSK-3β Activity in the Anterior Cingulate Cortex of Shank3b(−/−) Mice Contributes to Synaptic and Social Deficiency

Social deficiency is one of the core syndromes of autism spectrum disorders (ASD), for which the underlying developmental mechanism still remains elusive. Anterior cingulate cortex (ACC) plays a key role in integrating social information and regulating social behavior. Recent studies have indicated that synaptic dysfunction in ACC is essential for ASD social defects. In the present study, we investigated the development of synapses and the roles of glycogen synthase kinase 3β (GSK-3β), which mediates multiple synaptic signaling pathways in ACC by using Shank3b(−/−) mice (a widely used ASD mouse model). Our data revealed that Shank3b mutation abolished the social induced c-Fos expression in ACC. From 4 weeks post-birth, neurons in Shank3b(−/−) ACC exhibited an obvious decrease in spine density and stubby spines. The length and thickness of post-synaptic density (PSD), the expression of vesicular glutamate transporter 2 (vGlut2) and glutamate receptor 2 (GluR2), and the frequency of miniature excitatory post-synaptic currents (mEPSCs) were significantly reduced in Shank3b(−/−)ACC. Interestingly, the levels of phosphorylated GSK-3β (Ser9), which inhibits the activity of GSK-3β, decreased along the same time course as the levels of GluR2 increased in ACC during development. Shank3b mutation leads to a dramatic increase of pGSK-3β (Ser9), and decrease of pPSD95 (a substrate of GSK-3β) and GluR2. Local delivery of AAV expressing constitutively active GSK-3β restored the expression of GluR2, increased the spine density and the number of mature spines. More importantly, active GSK-3β significantly promoted the social activity of Shank3b(−/−) mice. These data, in together, indicate that decrease of GSK-3β activity in ACC may contribute to the synaptic and social defects of Shank3b(−/−) mice. Enhancing GSK-3β activity may be utilized to treat ASD in the future.