S-SCAM inhibits Axin-dependent synaptic function of GSK3β in a sex-dependent manner

S-SCAM/MAGI-2 gene duplication is associated with schizophrenia (SCZ). S-SCAM overexpression in the forebrain induces SCZ-like phenotypes in a transgenic (Tg) mouse model. Interestingly, S-SCAM Tg mice show male-specific impairments in synaptic plasticity and working memory. However, mechanisms underlying the sex-specific deficits remain unknown. Here we report that S-SCAM Tg mice have male-specific deficits in synaptic GSK3 beta functions, as shown by reduced synaptic protein levels and increased inhibitory phosphorylation of GSK3 beta. This GSK3 beta hyper-phosphorylation was associated with increased CaMKII activities. Notably, synaptic levels of Axin1, to which GSK3 beta binds in competition with S-SCAM, were also reduced in male S-SCAM Tg mice. We demonstrated that Axin-binding is required for the S-SCAM overexpression-induced synaptic GSK3 beta reduction. Axin stabilization using XAV939 rescued the GSK3 beta deficits and restored the temporal activation of GSK3 beta during long-term depression in S-SCAM overexpressing neurons. Interestingly, synaptic Axin2 levels were increased in female S-SCAM Tg mice. Female sex hormone 17 beta -estradiol increased Axin2 expression and increased synaptic GSK3 beta levels in S-SCAM overexpressing neurons. These results reveal the role of S-SCAM in controlling Axin-dependent synaptic localization of GSK3 beta. Moreover, our studies point out the pathological relevance of GSK3 beta hypofunction found in humans and contribute to understanding the molecular underpinnings of sex differences in SCZ.