Role of glia in sculpting synpatic fields during development and plasticity

描述（由申请人提供）：神经胶质细胞是神经系统的主要组成部分，一系列毁灭性疾病，如儿童脑室周围白质软化症、亚历山大病和脱髓鞘疾病，如多发性硬化症，都是由神经胶质功能障碍引起的。虽然神经胶质细胞最近被认为在神经元功能中起着关键作用，塑造突触连接，并为神经元提供必需的营养因子，但我们对调节其多种作用的分子机制的理解仍存在重大空白。这个建议采用了一个高度易于处理的系统，谷氨酸能果蝇神经肌肉连接（NMJ），以精细的细胞细节来研究神经胶质细胞生物学中的主要问题。我们的初步数据提供了令人信服的证据，证明神经胶质细胞在NMJs的可塑性中发挥作用，调节突触分化所需的重要途径，并通过修剪过程雕刻突触连接。在这个项目中，我们将（目标1）验证神经胶质细胞在NMJ扩展期间突触钮扣的伸展和收缩中起主要作用的假设，（目标2）验证神经胶质细胞调节NMJ的Wnt通路，并且这种调节对NMJ的发展至关重要的假设，以及（目标3）确定Draper信号通路在NMJ突触连接中的作用。我们期望这些研究将为活体动物突触和胶质细胞之间的细胞相互作用提供基本的见解，并揭示胶质细胞主动塑造突触连接的分子机制。项目的叙述

DESCRIPTION (provided by applicant): Glial cells are major constituents of the nervous system, and an array of devastating diseases, such as childhood periventricular leukomalacia, Alexanders Disease, and demyelinating diseases such as multiple sclerosis, arise from glial malfunction. Although glial cells have been recently recognized as playing key roles in neuronal function, sculpting synaptic connections, and providing essential trophic factors to neurons, there are major gaps in our understanding of the molecular mechanisms mediating their diverse actions. This proposal employs a highly tractable system, the glutamatergic Drosophila neuromuscular junction (NMJ), to investigate major questions in glial cell biology with exquisite cellular detail. Our preliminary data provides compelling evidence for a role of glial cells in the plasticity of NMJs, regulating an important pathway required for the differentiation of synapses, and sculpting synaptic connections by a process of pruning. In this project we will (Aim 1) test the hypothesis that glial cells play a primary role in the extension and retraction of synaptic boutons during NMJ expansion, (Aim 2) test the hypothesis that glial cells regulate a Wnt pathway at the NMJ and that this regulation is essential for NMJ development, and (Aim 3) determine the role of the Draper signaling pathway in sculpting synaptic connections at the NMJ. We expect that these studies will provide fundamental insights into the cellular interactions between synapses and glia in live animals and unravel molecular mechanisms by which glia actively sculpt synaptic connections. Project Narrative Glial cells, the major cell type in the human brain, have emerged as important regulators of brain development and physiology, and a number of devastating neurological diseases, such as multiple sclerosis or glioma, are associated with glial dysfunction. This proposal will explore how glia (in live animals) modulate the formation and modification of synapses, the basic functional units through which neurons communicate with other cell types. Our work will provide fundamental knowledge regarding how neurons and glia communicate during the modification of synapses, and is expected to provide important insights into how glial dysfunction might cause disease.