Roy Kristine, Murtie Joshua C, El-Khodor Bassem F, Edgar Nicole, Sardi S Pablo, Hooks Bryan M, Benoit-Marand Marianne, Chen Chinfei, Moore Holly, O'Donnell Patricio, Brunner Daniela, Corfas Gabriel
Neurobiology Program, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2007 May 8;104(19):8131-6. doi: 10.1073/pnas.0702157104. Epub 2007 May 1.
Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.
几种精神疾病与白质缺陷有关，这表明少突胶质细胞（OL）异常是这些疾病某些方面的基础。神经调节蛋白1（NRG1）及其受体erbB4在基因上与精神分裂症和双相情感障碍的易感性相关。体外研究表明，NRG1-erbB信号传导对OL发育很重要。为了测试erbB信号传导是否通过调节OL的结构或功能而导致精神疾病，我们分析了体内erbB信号传导在OL中被阻断的转基因小鼠。我们在此表明，erbB信号传导的缺失会导致OL数量和形态的变化、髓鞘厚度降低以及中枢神经系统轴突传导速度减慢。此外，这些转基因小鼠的多巴胺受体和转运体水平升高，并且行为改变与神经精神疾病一致。这些结果表明，白质缺陷可导致与神经精神疾病相关的多巴胺能功能和行为改变。
