Investigation on the regulation of synaptic transmission by glial molecules

本研究旨在阐明胶质细胞-神经元相互作用的分子机制，并基于胶质细胞对神经传递的调节来开发脑疾病的基本治疗方法。本研究主要完成了以下几个方面的工作：1）建立了一种研究胶质细胞在神经退行性变中作用的动物模型。小鼠适合于研究突触前结构缺失时神经胶质细胞功能的变化。我们采用定位克隆的方法对突变基因进行了鉴定。2）通过改变胶质细胞功能来治疗视网膜变性我们发现了一种新的光诱导感光细胞凋亡的途径，该途径涉及低亲和力神经营养素受体p75（p75 NTR）。视网膜变性上调p75 NTR和高亲和力神经营养因子受体TrkC在不同部位的Muller神经胶质细胞。外源性神经营养素-3（NT-3）可增加Muller细胞碱性成纤维细胞生长因子（bFGF）的产生，而神经生长因子（NGF）可减少bFGF的产生。p75 NTR的阻断阻止了bFGF的减少，并导致体内光感受器的结构和功能存活。3）其他我们发现PEPA是AMPA型谷氨酸受体的一种新型变构调节剂。PEPA影响脱敏，但不影响受体的失活。我们建立了缺乏神经胶质谷氨酸转运蛋白（GLAST）功能的小鼠模型，这些发现有助于进一步研究神经胶质细胞在神经传递中的作用。

In this study, we aimed to elucidate the molecular mechanism of glia-neuron interaction, and to develop essential therapy for brain diseases based on the glial regulation of neural transmission. We achieved investigations on the following subjects ;1) Identification of an animal model for investigating glial contribution on neurodegenerationThe gracile axonal dystrophy mouse is pathologically characterized by presynaptic degeneration at axon terminals. The mouse is suitable for investigating the functional change of glial cells during loss of presynaptic structures We employed a positional cloning approach to identify the gene for the mutation. We found that a segment of ubiquitin C-terminal hydrolase L1 gene is deleted in the mutant.2) Development of a new therapy of retinal degeneration by modification of glial cell functionWe demonstrate a novel pathway of light-induced photoreceptor apoptosis involving the low-affinity neurotrophin receptor p75 (p75NTR). Retinal degeneration upregulated both p75NTR and the high-affinity neurotrophin receptor TrkC in different parts of Muller glial cells. Exogenous neurotrophin-3 (NT-3) increased, but nerve growth factor (NGF) decreased basic fibroblast growth factor (bFGF) production in Muller cells, which can directly rescue photoreceptor apoptosis. Blockade of p75NTR prevented bFGF reduction and resulted in both structural and functional photoreceptor survival in vivo.3) MiscellaneousWe found that PEPA is a novel allosteric modulator of AMPA type glutamate receptors. PEPA affects desensitization but not deactivation of the receptors. We generated mice lacking the function of glial glutamate transporter, GLAST.These findings are useful for further investigation of glial contribution on neural transmission.