Development of Synaptic Specificity in the Mammalian Visual System

描述(申请人提供)：控制视觉回路形成的分子机制是什么？在整个哺乳动物中枢神经系统中，突触特异性最显著的结构相关性是板层特异性：神经元将其轴突和树突的树枝限制在特定的层，从而在给定的靶点内形成突触伙伴。在这个提案中，我们将重点了解阿尔法和贝塔视网膜神经节细胞(RGC)类型如何分别在上丘的深层和浅层形成精确的突触连接。RGCs的精确连接对正常运动和模式视觉感知至关重要，但决定这两个主要的视网膜神经节细胞如何连接到相应的板层靶神经元的分子机制仍然是个谜。我们假设，负责RGCs板层特异性突触选择的基因将由这两类主要的RGCs在其特定的板层连接形成的发育期选择性地表达。在我们的初步研究中，我们已经确定了α和βRGC的特定标记物，以及两个新的小鼠品系，它们在这些RGC类别中的每一个类别中都专门表达绿色荧光蛋白。我们将使用这些小鼠来解决以下问题：(1)与这两类功能不同的RGC相关的遗传学特征是什么？以及(2)是什么分子线索引导从这些功能不同的RGC类产生的轴突进入其主要靶点上丘内解剖上不同的层？然后，我们将利用这些信息来解决有关板层特异性发展的一个长期问题：RGC是在它们的靶板上形成最初精确的连接，还是形成最初弥漫的连接，然后消除不适当的连接？我们的最终目标是了解视觉突触连接在发育过程中是如何形成的，并将这些发现扩展到理解如何在青光眼、视网膜缺血和视神经炎等眼部疾病中诱导视觉系统连接在损伤后正确再生。对控制视觉回路形成的分子机制的了解将使我们能够开发新的治疗方法来促进它们的修复和再生，以恢复青光眼、视神经病变和损伤后的视力。

DESCRIPTION (provided by applicant): What are the molecular mechanisms that control the formation of visual circuits? Throughout the mammalian central nervous system, the most salient structural correlate of synaptic specificity is laminar specificity: neurons confine their axonal and dendritic arbors to particular layers and thereby, synaptic partners, within a given target. In this proposal, we will focus on understanding how alpha and beta retinal ganglion cell (RGC) types form their precise synaptic connections in the deep and superficial layers of the superior colliculus respectively. Precise wiring of RGCs is critical for proper motion and pattern visual perception, but the molecular mechanisms that dictate how these two major retinal ganglion cell classes connect to their appropriate laminar target neurons are still mysterious. We hypothesize that the genes responsible for laminar-specific synaptic choices of RGCs will be selectively expressed by these two main classes of RGCs during the developmental period when their specific laminar connections are forming. In our preliminary studies, we have identified specific markers of alpha and beta RGCs as well as two new mouse strains that express green fluorescent protein specifically in each of these RGC classes. We will use these mice to address the following questions: (1) What is the genetic profile associated with these two major classes of functionally distinct RGCs?, and (2) What are the molecular cues that direct axons arising from these functionally distinct classes of RGCs, into anatomically distinct layers within their major target, the superior colliculus? We will then use this information to address a longstanding question about the development of laminar specificity: do RGCs form connections in their target laminae that are initially precise or instead do they form connections that are initially diffuse and then eliminate inappropriate connections? Our ultimate goal is to understand how precise visual synaptic connections form during development and to extend those findings into an understanding of how to induce visual system connections to regenerate properly after injury in ocular diseases including glaucoma, retinal ischemia, and optic neuritis. An understanding of the molecular mechanisms that control the formation of visual circuits will allow us to develop new treatments to promote their repair and regeneration in order to restore vision in glaucoma, optic neuropathy, and after injury.