Development of Synaptic Specificity in the Mammalian Visual System

描述（由申请人提供）：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，突触特异性的最显著的结构相关性是层状特异性：神经元将其轴突和树突的乔木限制在特定的层中，从而在给定的靶点内形成突触伴侣。在这个建议中，我们将集中在了解α和β视网膜神经节细胞（RGC）类型如何形成精确的突触连接的深层和浅层的上级丘分别。RGC的精确布线对于适当的运动和模式视觉至关重要，但是决定这两种主要的视网膜神经节细胞如何连接到其适当的层状靶神经元的分子机制仍然是神秘的。我们假设，负责层特异性突触选择的RGC的基因将选择性地表达这两个主要类别的RGC在发育期间，当他们的特定的层连接正在形成。在我们的初步研究中，我们已经确定了α和β RGC的特异性标志物，以及两个新的小鼠品系，表达绿色荧光蛋白，特别是在每一个这些RGC类。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相关的遗传特征是什么？以及（2）是什么样的分子线索引导这些功能不同的RGCs产生的轴突进入其主要靶点上级丘内解剖学上不同的层？然后，我们将使用这些信息来解决一个长期存在的问题，关于发展的层特异性：RGCs形成连接，在其目标板最初是精确的，或者相反，他们形成连接，最初是弥漫的，然后消除不适当的连接？我们的最终目标是了解在发育过程中如何形成精确的视觉突触连接，并将这些发现扩展到了解如何诱导视觉系统连接在眼部疾病（包括青光眼，视网膜缺血和视神经炎）损伤后正确再生。了解控制视觉回路形成的分子机制将使我们能够开发新的治疗方法来促进其修复和再生，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.