Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
Neurosci Bull. 2013 Apr;29(2):251-9. doi: 10.1007/s12264-013-1323-1. Epub 2013 Apr 5.
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.
精神分裂症是一种主要影响年轻人（15 至 35 岁）的精神疾病，但病因仍未完全明确。最近，越来越多的证据表明脱髓鞘和/或少突胶质细胞功能障碍是其发病机制的一个重要特征。我们假设年轻人易发生脱髓鞘可能是导致精神分裂症发病的原因之一。在本研究中，我们使用了三个不同年龄的小鼠队列，即幼鼠（3 周龄）、年轻成年鼠（6 周龄）和中年鼠（8 月龄），给予含有 0.2% 脱髓鞘素（CPZ）的饮食 6 周，以建立急性脱髓鞘动物模型。然后，评估了年龄相关的对 CPZ 诱导的脱髓鞘易感性、行为结局以及与髓鞘形成相关的分子生物学变化。我们的研究结果表明：（1）CPZ 处理导致幼鼠和年轻成年鼠的胼胝体（与精神分裂症的病理生理学密切相关的区域）比中年鼠发生更严重的脱髓鞘；（2）幼鼠和年轻成年鼠的脱髓鞘程度更高与少突胶质细胞髓鞘碱性蛋白减少、CC-1 阳性成熟少突胶质细胞丢失增加以及星形胶质细胞激活水平升高有关；（3）CPZ 处理导致幼鼠和年轻成年鼠出现更明显的探索行为缺陷，而中年鼠则没有。综上所述，我们的数据表明存在与行为缺陷相关的年龄相关的脱髓鞘易感性，为更好地理解年轻人易患精神分裂症的原因提供了证据支持。
