Intercellular Communication in Retinal Development

视网膜回路对光信息的处理， 兴奋性和抑制性神经传递之间的联系视网膜神经节细胞的输出 视网膜神经节细胞（RGCs）到高级视觉中心的作用是由兴奋和抑制的平衡形成的 由它们的突触前伙伴双极细胞和无长突细胞提供。直接抑制 对RGC的反馈抑制和对突触前双极细胞的反馈抑制有助于最终 RGC的输出配置文件。之前，我们研究了兴奋性突触是如何 在RGC的树突状结构中以适当的密度建立， 发展并发现双极兴奋性传递的扰动 细胞导致RGC树突上的突触减少。这里我们 建议测试这一假设，即神经传递在发展过程中调节 抑制性输入向RGCs的发展，并协调RGCs的成熟 平衡这些细胞的兴奋和抑制。我们还将检验以下假设： 传递影响轴突末梢反馈抑制的发展 双极细胞。在目标1中，我们将确定抑制性的成熟组织 突触到RGC树突，并检查这些模式是如何出现的， 发展这将通过共聚焦和多光子成像RGCs来实现 带有荧光标记的抑制性突触后位点。这些实验需要 揭示了抑制性发展的时空关系， 单个RGC树突上的兴奋性突触。在目标2中，我们将直接测试 神经传递调节抑制性突触发育的假说 使用转基因小鼠的RGC，在转基因小鼠中， 明显压抑。在目标3中，我们将确定反馈抑制如何作用于杆 双极细胞的发展和确定的作用，神经传递的组装， 突触的实验。综合起来，这些结果 aims将推进我们对视网膜内层抑制回路如何发展的认识， 并帮助定义神经传递在获得视网膜神经元的正确连接中的作用。 电路或它们的错误布线在伤害和疾病。

The processing of light information by retinal circuits depends critically on the interplay between excitatory and inhibitory neurotransmission. The output of retinal ganglion cells (RGCs) to higher visual centers is shaped by a balance of excitation and inhibition provided by their presynaptic partners, bipolar cells and amacrine cells. Direct inhibition onto RGCs and feedback inhibition onto presynaptic bipolar cells contribute to the final output profile of the RGCs. Previously, we examined how excitatory synapses are established at appropriate densities across the dendritic arbor of RGCs during development and discovered that perturbation of excitatory transmission from bipolar cells results in a reduction in glutamatergic synapses on RGC dendrites. Here, we propose to test the hypothesis that neurotransmission during development regulates the development of inhibitory inputs onto RGCs, and coordinates the maturation of the balance of excitation and inhibition onto these cells. We will also test the hypothesis that transmission influences the development of feedback inhibition onto the axon terminals of the bipolar cells. In Aim 1, we will determine the mature organization of inhibitory synapses onto RGC dendrites and examine how these patterns arise during development. This will be achieved using confocal and multiphoton imaging of RGCs with fluorescently tagged inhibitory postsynaptic sites. These experiments are needed to reveal the spatial and temporal relationships of the development of inhibitory and excitatory synapses on the dendrites of individual RGCs. In Aim 2, we will directly test the hypothesis that neurotransmission regulates inhibitory synapse development on RGCs using transgenic mice in which either glutamatergic or GABAergic transmission is markedly suppressed. In Aim 3, we will determine how feedback inhibition onto rod bipolar cells develop and ascertain the role of neurotransmission in the assembly of this synapse using the transmission-perturbed mice. Taken together, the results from these aims will advance our knowledge of how inhibitory circuits in the inner retina develop, and help define the role(s) of neurotransmission in attaining the proper wiring of retinal circuits or their miswiring in injury and disease.