NMDA Receptor and Synaptic Plasticity in Retina

描述（由申请人提供）：NMDA受体（NR）介导的突触传递在出生后中枢神经系统（CNS）的许多区域的发育过程中受到调节。更重要的是，NRs在通过输入突触活动重塑或完善神经元回路方面发挥了重要作用。考虑到NR基因的表达、NR介导的视网膜神经节细胞电流以及RGC树突分层的成熟均受年龄和视觉经验的调节，我们假设NR介导的突触活性的年龄和活动依赖性调节在视网膜突触连接的成熟中起着关键作用。在本研究中，我们计划使用两种转基因/突变小鼠模型，其中NR的亚基2A （NR2A）基因缺失或富含NR2A的NR支架复合物（myosin Va）的关键元件突变，来验证这一假设。本研究的第一个目的是确定视网膜发育过程中RGCs上的突触分布和NRs的亚基组成是否受到视觉活动的调节，以及这种依赖于视觉活动的成熟过程在不同亚型RGCs之间是否存在差异。为此，将利用电生理和药理学方法对形态学鉴定的不同亚型RGCs的nr介导的突触电流的发育特征进行表征。第二个目标是确定NR2A表达阻滞或富含NR2A的nrrs的突触插入是否会改变NR2A介导的rgc突触电流的成熟。通过研究NR2A-/-和flailer小鼠RGC突触中NR介导的突触电流，可以验证RGC突触活性的年龄和活动依赖性变化是由于RGC突触中NR亚基组成从富含nr2b到富含NR2A的nrrs的发育转换引起的。第三个目标是通过使用NR2A-/-: Thy1-YFP和flailer Thy1-YFP小鼠，检测NR2A-/-: Thy1-YFP小鼠发育视网膜中不同亚型RGC的种群分布，确定nr介导的突触活性改变是否会干扰RGC突触连接的发展。本研究将为研究NRs在视网膜和中枢神经系统其他区域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觉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.