NEUROBIOLOGY

项目2，题为“Rett综合征的神经生物学”，重点是 青春期女童脑内神经元异常的发病机制 利用死后组织和一只新生小鼠的Rett综合征(RS) 准备时大脑皮层的变化与RS相似。 死后组织与小鼠模型的同源性研究 项目是协同的，因为鼠标模型可以控制和 以尸检组织不可能完成的方式进行处理，而我们的 在过去一段时间的支持工作中发现了惊人的相似之处 在这两者之间。该项目分为两个子项目，项目2a 主要与选定的神经递质突触的变化有关 标记物和项目2b侧重于细胞骨架的变化，特别是在 树突状标记微管相关蛋白。的具体目标 建议的放射自显影、免疫印迹和免疫细胞化学实验 在项目2a中将检验这样的假设：1.胆碱能障碍， 谷氨酸能和其他神经递质突触起着基础性作用 在RS的发病机制中起重要作用。在人类死后组织中，这些异常 在早期婴幼儿和儿童病例中最具活力。二、早起 大脑皮层胆碱能失神经后的分子事件 在最年轻的病例中观察到的GluR升高的原因 RS，并可能与突触相关蛋白的其他异常有关 包括谷氨酸转运体。大脑皮层胆碱能神经的丧失 以新生小鼠基底核损毁为模型。三、新生儿核 基底膜损伤加细胞外谷氨酸升高 注射醋酸铵会导致脑病、癫痫发作和 与RS极为相似的组织学改变。四、增强胆碱能 神经传递，要么通过增加乙酰胆碱水平，要么通过增强 新生期基底核神经元的再生可能 逆转模型中的皮质病理改变。我们主要研究的是神经生物学 脑组织中的RS既可以理解基本机制，也可以设计 理性治疗。

Project 2, entitled "the Neurobiology of Rett Syndrome" focuses on the pathogenesis of the neuronal abnormalities in the brains of girls with Rett Syndrome (RS) utilizing postmortem tissue and a neonatal mouse preparation with cerebral cortical changes that resemble those in RS. Study of both the postmortem tissue and the mouse model in the same project is synergistic because the mouse model can be controlled and manipulated in ways that are impossible with postmortem tissue, and our work over the last period of support has uncovered striking parallels between the two. The project is divided into two subprojects, Project 2a is primarily concerned with changes in selected neurotransmitter synaptic markers and Project 2b focuses on cytoskeletal changes, especially in the dendritic marker microtubule associated protein. The specific aims of proposed autoradiographic, Western Blot and immunocytochemical experiments in Project 2a will test the hypothesis that: I. Disorders of cholinergic, glutamatergic and other neurotransmitter synapses play a fundamental role in the pathogenesis of RS. In human postmortem tissues, the abnormalities will be most dynamic in early infancy and childhood cases. II. Early molecular events after cholinergic denervation in cerebral cortex contribute to the elevations in GluRs observed in the youngest cases of RS, and possibly for other abnormalities in synapse-related proteins including glutamate transporters. Cortical cholinergic denervation will be modeled by neonatal nucleus basalis lesions in mice. III. Neonatal nucleus basalis lesions plus elevated extracellular glutamate induced by administering ammonium acetate will produce encephalopathy, seizures, and histologic changes that strongly resemble RS. IV. Enhancing cholinergic neurotransmission, either by increasing acetylcholine levels or enhancing the regrowth of nucleus basalis neurons, in the neonatal period may reverse cortical pathology in the models. We focus on the neurobiology of RS in brain tissue both to understand basic mechanisms and to design rational therapy.