GABAc Receptors & Mouse Retinal Ganglion Cell Responses

描述(由申请人提供)：视觉需要将视野的许多方面整合成一个有机整体，供有机体用来导航其环境。哺乳动物的视网膜是一个层状结构，每一层由几种细胞类型组成，这些细胞类型组合在一起定义了视网膜神经节细胞(RGC)的反应特性，RGC将信号传输到大脑。视觉场景的许多方面由视网膜内的两条平行路径编码，这两条路径要么检测光强度的增加，要么检测光强度的减少。有许多类型的RGC，它们的反应由它们收到的输入来定义。形成它们反应特性的一个关键因素是抑制，像大脑的其他区域一样，它是由甘氨酸和伽马氨基丁酸(GABA)介导的。GABA抑制是由三种受体GABAA、GABAB和GABAC介导的，所有这些受体都存在于视网膜中。因此，一个挑战是确定这些抑制性和兴奋性输入如何塑造视网膜节细胞的反应。实现这一目标的一个新工具是操纵小鼠基因组并选择性地移除特定输入的能力，然后可以评估其对视网膜节细胞的影响。然而，与猫、兔和灵长类动物的大量文献不同，人们对小鼠视网膜节细胞的基本特性知之甚少。这项建议的目的是表征小鼠视网膜神经节细胞在体内和体外的反应特性，特别是确定GABACR介导的输入在塑造反应中所起的作用。具体目的是(1)确定从遗传上消除GABACR介导的抑制对体内记录的RGC反应特性子集的影响，以及(2)将一组不同的RGC的结构和功能联系起来，并确定消除GABACR介导的输入对这些细胞类型中每一种类型的反应特性的影响。这些数据将增强我们对抑制在塑造视网膜输出细胞反应中的作用的理解，从而加深我们对视野中信息整合的重要方面的理解。

DESCRIPTION (provided by applicant): Vision requires the integration of many aspects of the visual field into a cohesive whole that is used by the organism to navigate its environment. The mammalian retina is a laminar structure and each layer is populated by several cell types that combine to define the response properties of the retinal ganglion cells (RGCs), which transmit the signal to the brain. The many aspects of the visual scene are encoded by two parallel pathways within the retina that either detect increases or decreases in light intensity. There are many types of RGCs and their responses are defined by the inputs they receive. One key element in shaping their response properties is inhibition, which like other regions of the brain is mediated by glycine and gamma amino butyric acid (GABA). GABA inhibition is mediated by three receptors, GABAA, GABAB and GABAC, all of which are present in the retina. One challenge then is to determine how each of these inhibitory and excitatory inputs shapes the responses of the RGCs. A new tool towards attaining this goal is the ability to manipulate the mouse genome and selectively remove specific inputs, the effect of which then can be assessed on the RGCs. However, unlike the extensive literature for cat, rabbit and primate, relatively little is known about the fundamental properties of murine RGCs. The goal of this proposal is to characterize the response properties of mouse RGCs both in vivo and in vitro, and in particular determine the role that GABACR-mediated input plays in shaping the responses. The specific aims are (1) to determine the effect of eliminating, genetically, GABACR-mediated inhibition on a subset of RGC response properties recorded in vivo, and (2) correlate structure and function of a diverse set of RGCs, and determine the impact of eliminating GABACR-mediated input on the response properties of each of these cell types. These data will enhance our understanding of the role of inhibition in shaping the response of the output cells of the retina, and therefore important aspects of integration of information in the visual field.