Investigation on the regulation of synaptic transmission by glial molecules

在本研究中，我们旨在阐明神经胶质-神经元相互作用的分子机制，并基于神经胶质对神经传递的调节开发脑疾病的必要治疗方法。我们对以下主题进行了调查：1)研究胶质细胞在神经变性中的作用的动物模型的确定细轴突营养不良小鼠的病理特征是轴突末端的突触前变性。小鼠适合研究突触前结构缺失时神经胶质细胞的功能变化。我们采用定位克隆方法鉴定突变基因。我们发现在突变体中缺失了泛素c端水解酶L1基因的一个片段。2)通过改变神经胶质细胞功能来治疗视网膜变性的新方法的发展我们发现了一种涉及低亲和力神经营养因子受体p75 （p75NTR）的光诱导光受体凋亡的新途径。视网膜变性上调Muller胶质细胞不同部位的p75NTR和高亲和力神经营养因子受体TrkC。Muller细胞中外源性神经营养因子-3 （NT-3）增加，而神经生长因子（NGF）减少碱性成纤维细胞生长因子（bFGF）的产生，可直接挽救光感受器凋亡。阻断p75NTR可阻止bFGF的减少，并导致体内结构和功能光感受器的存活。我们发现PEPA是AMPA型谷氨酸受体的一种新的变构调节剂。PEPA影响脱敏，但不影响受体的失活。我们制造了缺乏胶质谷氨酸转运体GLAST功能的小鼠。这些发现有助于进一步研究神经胶质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.