中枢髓鞘晚期发育的关键分子机制及其与精神性疾病相关性的研究

Adolescence is the critical period for central nervous system (CNS) to develop completely and mature. Meanwhile, it is the onset window for most of psychiatric disorders. CNS myelin, generated by mature oligodendrocytes, develops after birth to several decades, with the fastest expansion in adolescence. Abnormalities of the structures, component proteins and regulating molecules in white matter have been frequently detected in patients with different psychiatric disorders. However, there is no convincing evidence for either dysmyelination is one of the pathological features of psychiatric disorders or dysmyelination in CNS causes symptoms of the diseases. Dysregulation and SNPs of tyrosine kinase receptor ErbBs and their ligands have been implicated in psychiatric disorders, while mutation in the receptors, ligands or regulators in ErbBs signaling pathway causes abnormal behaviors in mutant mice. Moreover, ErbBs pathway is critical for peripheral myelination. Thus, we propose to study the contribution of ErbBs signaling to central myelination, as well as assess the behavioral performances of animals with myelin damage or under the control of altered ErbBs pathway. Results of the study will provide the direct evidence for whether disrupted central myelination is associated with pathophysiology or the symptoms of psychiatric disorders. Moreover, discovery of the critical molecular mechanisms for central myelination will provide the targets for intervention of demyelinating diseases and/or psychiatric disorders.

青春期是中枢神经系统成熟的关键时期，也是大多数精神性疾病发作起始的时期。由分化成熟的少突胶质细胞形成的中枢髓鞘需要几十年时间完全发育成熟，而青春期是其发育最迅速的时候。中枢白质结构，髓鞘蛋白和髓鞘调节因子的失调是精神性疾病中的常见现象，但中枢髓鞘受损是否精神性疾病的病理及病症的原因之一迄今仍缺少证据。酪氨酸激酶受体ErbBs及其配体的表达改变或单核苷酸多态性与精神性疾病具有相关性。ErbBs信号通路的受体，配体或调节因子的突变均导致动物出现与精神性疾病相似的异常行为。本项目将研究作为外周髓鞘生成的关键调节机制的ErbBs通路在中枢髓鞘发育中的贡献，并通过行为学实验鉴定中枢髓鞘直接受损或在突变的ErbBs通路调节下对动物高级脑功能的影响，从而提供中枢髓鞘与精神性疾病病理和病症相关与否的直接证据。同时，揭示中枢髓鞘晚期发育调控的关键分子机制也将为脱髓鞘疾病和精神性疾病提供防治的靶点。

中枢神经系统晚期发育的关键事件，包括髓鞘形成和神经元间突触建立，是大脑高级功能正常行使的基础。导致中枢神经系统发育后期的成熟和修饰缺陷的因素往往导致个体认知、情感、社交等障碍。酪氨酸激酶受体ErbB的信号通路已被证实对外周髓鞘的建立不可或缺，也可能参与突触功能的调节，但其对中枢髓鞘或突触的细胞特异性调节机制尚有许多待解之谜。我们利用基因工程小鼠的优势，细胞特异性和时间特异性地突变调节ErbB信号通路的关键蛋白，或转入显性负性的ErbB受体突变体，从而研究ErbB信号通路对中枢神经系统晚期发育的关键调节机制。初步研究结果确定了ErbB受体及其调节分子Erbin对中枢神经系统晚期发育的关键过程---髓鞘发育和突触建立---有着极其重要的调节作用，肯定了深入研究ErbB信号通路功能及其调节机制的必要性。研究结果提示ErbB受体和其调节分子对中枢神经系统不同发育阶段的调节可能有时间特异性和细胞特异性。