RESUMO
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 GSK3ß functions, as shown by reduced synaptic protein levels and increased inhibitory phosphorylation of GSK3ß. This GSK3ß hyper-phosphorylation was associated with increased CaMKII activities. Notably, synaptic levels of Axin1, to which GSK3ß 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 GSK3ß reduction. Axin stabilization using XAV939 rescued the GSK3ß deficits and restored the temporal activation of GSK3ß during long-term depression in S-SCAM overexpressing neurons. Interestingly, synaptic Axin2 levels were increased in female S-SCAM Tg mice. Female sex hormone 17ß-estradiol increased Axin2 expression and increased synaptic GSK3ß levels in S-SCAM overexpressing neurons. These results reveal the role of S-SCAM in controlling Axin-dependent synaptic localization of GSK3ß. Moreover, our studies point out the pathological relevance of GSK3ß hypofunction found in humans and contribute to understanding the molecular underpinnings of sex differences in SCZ.