NMDA Receptor and Synaptic Plasticity in Retina

NMDA 受体和视网膜突触可塑性

• 批准号: 6984419
• 负责人: Ning Tian
• 金额: $ 16.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984419
• 关键词: NMDA receptors; central nervous system; electrophysiology; eye pharmacology; genetically modified animals; growth /development; laboratory mouse; neural plasticity; neuroanatomy; receptor expression; retina; retinal ganglion; synapses; visual stimulus

DESCRIPTION (provided by applicant): NMDA receptor (NR)-mediated synaptic transmission is regulated during postnatal development in many regions of central nervous system (CNS). More importantly, NRs can play an essential role in enabling neuronal circuits to be reshaped or refined by input synaptic activity. Given that the expression of NR genes, NR-mediated currents of retinal ganglion cells (RGCs) and the maturation of RGC dendritic stratification are all regulated by age and visual experience, we hypothesize that the age- and activity-dependent regulation of NR-mediated synaptic activity plays a critical role in the maturation of retinal synaptic connectivity. In this proposed study, we plan to use two transgenic/mutant mouse models, in which either the gene of subunit 2A (NR2A) of NR is deleted or a key element of the NR2A-rich NR scaffold complex (myosin Va) is mutated, to test this hypothesis. The first goal of this proposed study is to determine whether the synaptic distribution and the subunit composition of NRs on RGCs are regulated by visual activity in developing retina and whether this activity-dependent maturational process various between different subtypes of RGCs. Toward this end, the developmental profile of NR-mediated synaptic currents of different subtypes of morphologically identified RGCs will be characterized using electrophysiological and pharmacological approaches. The second goal is to determine whether block of NR2A expression or synaptic insertion of NR2A-rich NRs alters the maturation of NR-mediated synaptic currents of RGCs. The hypothesis that the age- and activity-dependent changes of RGC synaptic activity result from the developmental switch of NR subunit composition from NR2B-rich to NR2A-rich NRs at RGC synapses will be tested by examining the NR-mediated synaptic currents of RGCs from developing NR2A-/- and flailer mice. The third goal is to determine whether alteration of NR-mediated synaptic activity perturbs the development of RGC synaptic connectivity by examining the population distribution of different subtypes of RGCs in developing retinas with altered NR-mediated synaptic activity using NR2A-/-: Thy1-YFP and flailer Thy1-YFP mice. This study will identify valuable mouse models for the study of the roles of NRs in synaptic plasticity of retina and other areas of CNS. The results will also provide insights to how maturation of retinal synaptic circuitry could affect our interpretation of activity-dependent synaptic plasticity in visual cortex.

描述（由申请人提供）：NMDA受体（NR）介导的突触传播在产后发育过程中受到许多中枢神经系统（CNS）（CNS）的调节。更重要的是，NRS可以通过输入突触活动来重塑或完善神经元回路起着至关重要的作用。鉴于NR基因的表达，视网膜神经节细胞（RGC）的NR介导的电流和RGC树突分层的成熟都受年龄和视觉体验的调节，我们假设NR介导的年龄和活动依赖性的NR介导的触发活性在成熟中扮演着关键的维持式连接性。在这项拟议的研究中，我们计划使用两种转基因/突变小鼠模型，其中删除了NR的亚基2a（NR2A）基因，或者将富含NR2A的NR NR支架复合物（肌动蛋白VA）的关键要素进行突变，以检验该假设。这项拟议的研究的第一个目标是确定RGC上NRS的突触分布和亚基组成是否受开发视网膜的视觉活动调节，以及这种活动依赖性的成熟过程是否在RGC的不同子类型之间存在各种不同的成熟过程。为此，使用电生理和药理方法来表征NR介导的不同亚型的NR介导的突触电流的发育曲线。第二个目标是确定富含NR2A的NRS的NR2A表达或突触插入是否会改变RGC的NR介导的突触电流的成熟。 RGC突触活动的年龄和活动依赖性变化的假设是由NR亚基组成从RGC突触中从NR2B富含NR2B富含NR2B的NRS到富含NR2B的NRS的发展，可以通过检查从开发NR2A的NR2A-// - / - / - / - 和Flailer小鼠中的NR介导的RGC的NR介导的RGC的突触。第三个目标是确定NR介导的突触活性的改变是否通过检查RGC突触连通性的发展是否通过检查RGC的不同亚型的种群分布在开发带有NR2A-thy1-Yfp和Flailer Thy1-yfp小鼠的NR2A - / - ：THY1-YFP和Flailer thy1-yfp和Flailer thy1-yfp小鼠中开发带有NR介导的突触活性的视网膜中。这项研究将确定有价值的小鼠模型，以研究NR在视网膜和其他中枢神经系统区域的突触可塑性中的作用。结果还将为视网膜突触回路的成熟如何影响我们对视觉皮层中活动依赖性突触可塑性的解释提供见解。