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.
