Studies of the effect of DISC1 variants on abnormal metabolic phenotypes in schizophrenic model mice

Abstract

The connection between mental disorders and metabolic syndrome (MetS) such as type 2 diabetes has been evident lately. The mechanism for the comorbidity between mental disorder and MetS is not completely understood and most studies have explained it as side-effects of anti-psychotic drugs. However, it has been reported that drug-naïve patients with severe mental disorders suffered from MetS. This means that genetic factors are involved in the comorbidity between them. In this study, we identified novel effects of DISC1, a genetic susceptibility factor for schizophrenia, on abnormal metabolic phenotypes in schizophrenic model mice. Two different DISC1 mutant mice showed reduced glucose tolerance, a series of indexes for β-cell function and insulin sensitivity. In addition, we found that some phosphokinases’ activities are related to the cellular metabolism, GSK3β, IR and AMPKα, were altered in the cultured cortical neurons of DISC1 mutant mice. Furthermore, it was shown that DISC1 interacted strongly with AMPKα and modulated the activity of AMPKα in co-immunoprecipitation (co-IP) assays and phospho blots. Considering the results of the relation between DISC1 and AMPKα, a possible mechanism is that the sustained activation of AMPK by DISC1 can result in apoptosis in pancreatic β-cells. Collectively, this study suggests that abnormal DISC1 may increase a risk of MetS but further study is needed to define the exact mechanism of DISC1-induced MetS in DISC1 mutant mice.