Cell communication in the vertebrate retina

描述(由申请人提供)：这项研究提案是对D-丝氨酸在脊椎动物视网膜中作为神经胶质-神经元相互作用的媒介所起作用的广泛调查。在这项A1修订中，赠款和预算的范围大大缩小到以前目标的一个子集。初步证据表明，D-丝氨酸是由Muller细胞和星形胶质细胞合成和释放的，这种释放是由视网膜胶质细胞固有的AMPA受体的谷氨酸激活所介导的；D-丝氨酸作为内源性激动剂与谷氨酸一起激活视网膜内神经节和无长突细胞中的NMDA受体。本申请中描述的研究旨在检验D-丝氨酸是控制视网膜神经节细胞兴奋性的主要因素，并通过这一作用调节视网膜网络操作的假设。我们还将探索D-丝氨酸除了改变NMDA受体敏感性外，还具有细胞作用的可能性。本申请中描述的研究旨在研究D-丝氨酸的释放、摄取和储存及其生理作用。甘氨酸作为NMDA共激动剂的作用也将利用高亲和力甘氨酸摄取系统的有效阻断剂进行研究。我们将利用完整视网膜中单个细胞的电生理记录以及对单个分离的Muller细胞的研究来探索这些机制。内源性D-丝氨酸的释放将使用一种新的在线毛细管电泳法进行。这项研究计划将利用脊椎动物视网膜的独特功能，使其成为研究D-丝氨酸及其在视网膜网络操作和视网膜动态平衡中的重要性的理想靶点。了解D-丝氨酸在视网膜功能中的重要性是至关重要的，因为现在患者正在接受大剂量D-丝氨酸的精神障碍治疗。

DESCRIPTION (provided by applicant): This research proposal is a broad investigation into the role that D-serine plays as a mediator of glial-neuronal interactions in the vertebrate retina. In this A1 revision, the scope of the grant and the budget has been significantly reduced to a subset of the previous aims. Preliminary evidence suggests that D-serine is synthesized and released by Muller cells and astrocytes and that this release is mediated by glutamate activation of AMPA receptors intrinsic to the retinal gila; D-serine serves as the endogenous coagonist with glutamate to activate NMDA receptors found in ganglion and amacrine cells of the inner retina. The research described in this application is designed to test the hypothesis that D-serine is a major factor in controlling the excitability of retinal ganglion cells and serves to modulate the retinal network operations through this action. We will also explore the possibility that D-serine has cellular actions other than that of altering NMDA receptor sensitivity. The research described in this application is designed to study the release, uptake and storage of D-serine as well as its physiological actions. The role of glycine as an NMDA coagonist will also be studied using effective blocking agents for high affinity glycine uptake systems. We will explore these mechanisms using electrophysiological recordings from single cells in the intact retina as well as studies of single dissociated Muller cells. Release of endogenous D-serine will be done using a new on-line capillary electrophoresis concept. This research plan will take advantage of the unique features of the vertebrate retina which make it an ideal target for studies of D-serine and its importance in retinal network operations and homeostasis of the retina. It is essential to understand the importance of D-serine in retinal function, as patients are now being treated for psychiatric disorders with high doses of D-serine.