S-SCAM inhibits Axin-dependent synaptic function of GSK3β in a sex-dependent manner. Sci Rep 2022 Mar 08;12(1):4090
Date
03/10/2022Pubmed ID
35260764Pubmed Central ID
PMC8904762DOI
10.1038/s41598-022-08220-1Scopus ID
2-s2.0-85126076405 (requires institutional sign-in at Scopus site) 1 CitationAbstract
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 GSK3β functions, as shown by reduced synaptic protein levels and increased inhibitory phosphorylation of GSK3β. This GSK3β hyper-phosphorylation was associated with increased CaMKII activities. Notably, synaptic levels of Axin1, to which GSK3β 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 GSK3β reduction. Axin stabilization using XAV939 rescued the GSK3β deficits and restored the temporal activation of GSK3β during long-term depression in S-SCAM overexpressing neurons. Interestingly, synaptic Axin2 levels were increased in female S-SCAM Tg mice. Female sex hormone 17β-estradiol increased Axin2 expression and increased synaptic GSK3β levels in S-SCAM overexpressing neurons. These results reveal the role of S-SCAM in controlling Axin-dependent synaptic localization of GSK3β. Moreover, our studies point out the pathological relevance of GSK3β hypofunction found in humans and contribute to understanding the molecular underpinnings of sex differences in SCZ.
Author List
Kearney G, Grau D, Nieves Torres D, Shin SM, Lee SHAuthor
Sang H. Lee PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptor Proteins, Signal TransducingAnimals
Axin Protein
Female
Glycogen Synthase Kinase 3 beta
Guanylate Kinases
Male
Mice
Neuronal Plasticity
Neurons
Sex Factors
Signal Transduction
