NMDA Receptor and Synaptic Plasticity in Retina

描述（由申请人提供）：NMDA受体（NR）介导的突触传递在中枢神经系统（CNS）的许多区域的出生后发育过程中受到调节。更重要的是，NRs可以在通过输入突触活动重塑或改善神经元回路方面发挥重要作用。鉴于NR基因的表达，NR介导的电流的视网膜神经节细胞（RGC）和RGC树突分层的成熟都受到年龄和视觉经验的调节，我们假设年龄和活动依赖性调节NR介导的突触活动在视网膜突触连接的成熟中起着至关重要的作用。在这项拟议的研究中，我们计划使用两个转基因/突变小鼠模型，其中NR的亚基2A（NR 2A）的基因缺失或富含NR 2A的NR支架复合物（肌球蛋白Va）的关键元件突变，以验证这一假设。本研究的第一个目标是确定视网膜节细胞上的神经元受体的突触分布和亚基组成是否受视网膜发育过程中视觉活动的调节，以及这种活动依赖性成熟过程是否在不同亚型的视网膜节细胞之间存在差异。为此，NR-介导的突触电流的不同亚型的形态学鉴定的RGCs的发育概况的特点是使用电生理学和药理学的方法。第二个目标是确定NR 2A表达的阻断或富含NR 2A的NR的突触插入是否改变了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是由RGC突触处NR亚基组成从富含NR 2B到富含NR 2A的NR的发育转换引起的，这一假设将通过检查来自发育中的NR 2A-/-和flailer小鼠的RGC的NR介导的突触电流来检验。第三个目标是通过使用NR 2A-/-：Thy 1-YFP和Flailer Thy 1-YFP小鼠检查具有改变的NR介导的突触活性的发育视网膜中不同RGC亚型的群体分布来确定NR介导的突触活性的改变是否扰乱RGC突触连接的发育。本研究将为研究神经元受体在视网膜和中枢神经系统其他区域的突触可塑性中的作用提供有价值的小鼠模型。这些结果也将为视网膜突触回路的成熟如何影响我们对视皮层活动依赖性突触可塑性的解释提供见解。

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.