NMDA Receptor and Synaptic Plasticity in Retina

描述(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提炼神经元回路方面发挥重要作用。由于NR基因的表达、视网膜神经节细胞(RGCs)的NR介导的电流以及RGC树突分层的成熟都受年龄和视觉经验的调节，我们推测NR介导的突触活性的年龄和活动依赖性的调节在视网膜突触连接的成熟中起着关键作用。在这项拟议的研究中，我们计划使用两个转基因/突变小鼠模型来验证这一假设，在这两个模型中，NR亚单位2A(NR2A)的基因缺失或富含NR2A的NR支架复合体的关键元件(肌球蛋白Va)发生突变。这项研究的第一个目的是确定RGC上NRs的突触分布和亚单位组成是否受发育中视网膜的视觉活动调节，以及这种依赖活动的成熟过程是否在RGCs的不同亚型之间有所不同。为此，我们将用电生理学和药理学的方法来研究不同亚型视网膜神经节细胞中NR介导的突触电流的发育特征。第二个目标是确定阻断NR2A表达或突触插入富含NR2A的NRs是否改变了NR介导的RGCs突触电流的成熟。RGC突触活性的年龄和活性依赖改变是由于RGC突触的NR亚单位组成从富含NR2B的NRs向富含NR2A的NRs的发育转换所致，这一假说将通过检测发育中的NR2A-/-和Fliffer小鼠RGCs的NR介导的突触电流来检验。第三个目标是通过使用NR2a-/-：Thy1-YFP和Flailer Thy1-YFP小鼠来检测发育中不同亚型的RGC在NR介导的突触活性改变的视网膜中的种群分布，以确定NR介导的突触活性的变化是否扰乱了RGC突触连接的发展。本研究将为研究NRS在视网膜和CNS其他区域突触可塑性中的作用提供有价值的小鼠模型。这些结果还将为视网膜突触电路的成熟如何影响我们对视觉皮质中活性依赖的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.