title: Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit.
abstract: 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-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.
authors.affiliation: Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
authors.forename: Hongkai
authors.initials: H
authors.lastname: Wang
authors.forename: Chengren
authors.initials: C
authors.lastname: Li
authors.forename: Hanzhi
authors.initials: H
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Mei
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Shen
authors.forename: Lan
authors.initials: L
authors.lastname: Xiao
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002614:Chelating Agents / Q000633:toxicity*; D015331:Cohort Studies; D003337:Corpus Callosum / Q000378:metabolism / Q000473:pathology; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000150:complications*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein; D001523:Mental Disorders / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D002614:Chelating Agents; D005904:Glial Fibrillary Acidic Protein; C499047:Mbp protein, mouse; D004676:Myelin Basic Protein; D003471:Cuprizone
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