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MK-801 induces schizophrenic behaviors through downregulating Wnt signaling pathways in male mice
Jianfeng Yu1, Dake Qi, Mengjuan Xing
1Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China.
Abstract:
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 7days 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.
Insights
Schizophrenia may involve Wnt signaling pathway disruptions. Increased adenomatous polyposis coli (APC) protein in the brain may contribute to neurite growth abnormalities seen in schizophrenia.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Wnt signaling is crucial in neuropsychiatric disorders, but its role in schizophrenia remains unclear.
- Previous findings linked adenomatous polyposis coli (APC) gene variants and elevated APC mRNA in leukocytes to schizophrenia.
- APC acts as a negative regulator of the Wnt signaling pathway.
Purpose of the Study:
- To investigate the Wnt signaling pathway's role in schizophrenia pathogenesis.
- To examine the impact of MK-801-induced schizophrenia-like symptoms on Wnt signaling components in mice.
- To determine the effect of APC on neurite growth in vitro.
Main Methods:
- Schizophrenia-like symptoms were induced in mice using MK-801.
- Wnt signaling pathway components were analyzed in the prefrontal cortex (PFC) and ventral tegmental area (VTA) of mice.
- APC siRNA was used in SK-N-SH and PC12 cell cultures to assess neurite growth.
Main Results:
- MK-801 treatment increased inhibitory phosphorylation of GSK-3beta but not beta-catenin phosphorylation in mouse PFC and VTA.
- APC mRNA and protein levels were elevated in the PFC and VTA of MK-801-treated mice, correlating with increased beta-catenin phosphorylation.
- Increased total dendritic length was observed in the PFC and VTA of MK-801-treated mice.
- APC protein was found to promote neurite growth in cultured cells.
Conclusions:
- MK-801-induced schizophrenia is associated with an attenuated Wnt signaling pathway in the brain.
- Elevated APC protein levels may contribute to schizophrenia pathology by promoting neurite growth.
- Further research into the Wnt signaling pathway and APC's role is warranted for understanding schizophrenia.
