MK-801 induces schizophrenic behaviors through downregulating Wnt signaling pathways in male mice

Wnt signaling is important in various neuropsychiatric diseases. However, its actions on modulating schizophrenia are largely unknown. Our previous study found that three SNPs in adenomatous polyposis coli (APC), a negative regulator of the Wnt signaling, were associated with schizophrenia, and the mRNA levels of APC in blood leucocytes of patients with schizophrenia were significantly increased. This prompted us to further investigate the effects of Wnt signaling components on the pathogenesis of schizophrenia. In our current study, mouse schizophrenia was induced by i.p. injection of MK-801 for 7 days and the brain prefrontal cortex (PFC) and ventral tegmental area (VTA) were isolated to investigate the Wnt signaling pathway. Compared with control, schizophrenic mice had increased inhibitory phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) in PFC and VTA, which is disassociated with augmented beta-catenin phosphorylation. However, APC mRNA and protein in the PFC and VTA isolated from the schizophrenic group were increased and matched with increased beta-catenin phosphorylation. The total dendritic length was significantly increased in both PFC and VTA from MK-801-treated mice compared to control. By using cultured SK-N-SH and PC12 cells with and without transfection of APC siRNA, we found that the APC protein facilitates neurite growth in vitro. Our data suggested that MK-801-induced schizophrenia is associated with attenuated Wnt signaling pathway in the brain, which may be due to augmented APC protein during schizophrenia. APC facilitates neurite growth, potentially contributing to the pathology of schizophrenia. Crown