Demyelination in the hippocampus and its correlation with altered behaviors of the cuprizone-induced mouse model of schizophrenia

Abstract:

Objective：To investigate the correlation between changes of the volume of the myelinated nerve fibers in mouse hippocam－pus and altered behaviors with a novel schizophrenia-like animal model which was established by treating C57BL/6 mice with cupri－zone（CPZ）. Methods：Totally 19 male C57BL/6 mice were randomly divided into experimental group and control group. Experimental mice received powdered rodent chow containing 0.2% CPZ for 6 weeks to establish a schizophrenia-like mouse model，while control mice were fed with standard rodent chow for 6 weeks. Open field test，elevated plus maze test，Morris water maze test，turn-club test and hole board test were used to estimate behavior changes. Anti-myelin basic protein（MBP） immunohistochemistry stain－ing and transmission electron microscope were used to investigate the structure changes of myelin sheaths. Volume density and total volume of the myelinated nerve fibers in the hippocampus were investigated with the stereological methods. Correlation between altered behaviors and changed myelinated nerve fibers in the hippocampus was estimated with correlation analysis. Results：Mean weight was significantly decreased in experiment group than in control group（P<0.05）.Behavior test results indicated that nervous re－sponse and spatial cognitive ability of experimental mice was significantly worse than those of control mice（P=0.018，P=0.037），while action ability，exploration ability and working memory of experimental mice were not significantly different from those of control mice（P=0.443，P=0.306，P=0.462）. MBP positive nerve fibers in the hippocampus were apparently fewer than in experimental mice than in control mice. Demyelination of the myelinated nerve fibers in the hippocampus was observed under transmission electron microscope. Volume of hippocampus of experimental mice was not significantly changed compared with that of control group（P=0.955），while total volume of the mylinated nerve fibers in the hippocampus of experimental mice was significantly less than that of the control mice（P=0.009）. Correlation analysis results suggested that the close-arm distance rate was significantly and positively correlated with volume of the myelinated nerve fibers in the hippocampus（rs=0.83，P=0.003），while the open-arm distance rate was negatively correlated with volume of the myelinated nerve fibers in the hippocampus（rs=-0.65，P=0.043）. Conclusions：The study further demonstrates that CPZ-treated mice display schizophrenia-like behavior changes and mylinated nerve fibers in its hippocampus undergo pathological change of demylination. Moreover，present results indicate that changed volume of the mylinated nerve fibers in the hippocampus is correlated with altered behaviors.