Cuprizone-induced demyelination in mice: age-related vulner-ability and exploratory behavior deficit  

作　　者：Hongkai Wang Chengren Li Hanzhi Wang Feng Mei Zhi Liu Hai-Ying Shen Lan Xiao 

机构地区：[1]Department of Histology and Embryology,Chongqing Key Laboratory of Neurobiology,Third Military Medical University [2]Robert Stone Dow Neurobiology Laboratories,Legacy Research Institute

出　　处：《Neuroscience Bulletin》2013年第2期251-259,共9页神经科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China (81071084);the International Science &Technology Cooperation Program of China (2010DFB30820);the Natural Science Foundation of Chongqing Municipality, China(2010DBF30820)

摘　　要：Schizophrenia is a mental disease that mainly affects young individuals （15 to 35 years old） but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile （3 weeks）, young-adult （6 weeks） and middle-aged （8 months）, were subjected to a 6-week diet containing 0.2% cuprizone （CPZ） to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated： （1） CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; （2） the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1- positive mature oligodendrocytes, and higher levels of astrocyte activation; and （3） CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-relatedvulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.Schizophrenia is a mental disease that mainly affects young individuals （15 to 35 years old） but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile （3 weeks）, young-adult （6 weeks） and middle-aged （8 months）, were subjected to a 6-week diet containing 0.2% cuprizone （CPZ） to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated： （1） CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; （2） the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1- positive mature oligodendrocytes, and higher levels of astrocyte activation; and （3） CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-relatedvulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

关 键 词：SCHIZOPHRENIA OLIGODENDROCYTES agedemyelination CUPRIZONE 

分 类 号：R749.3[医药卫生—神经病学与精神病学]