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枝限制在特定的层内，因此，突触伴侣在给定的目标内。在这个提议中，我们将重点了解α和β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的精确连接对于正常运动和模式视觉感知至关重要，但决定这两种主要视网膜神经节细胞类别如何连接到适当的层流目标神经元的分子机制仍然是神秘的。我们假设，在RGCs形成特定层流连接的发育时期，这两类主要的RGCs会选择性地表达负责其层流特异性突触选择的基因。在我们的初步研究中，我们已经确定了α和β RGC的特异性标记，以及两种新的小鼠品系，它们在这些RGC类别中特异性表达绿色荧光蛋白。我们将使用这些小鼠来解决以下问题：(1)与这两大类功能不同的RGCs相关的基因图谱是什么？(2)是什么分子线索引导轴突从这些功能上不同的RGCs类别中产生，进入其主要目标上丘的解剖上不同的层？然后，我们将利用这些信息来解决一个长期存在的关于层流特异性发展的问题：rgc在其目标层流中形成的连接最初是精确的，还是它们形成的连接最初是分散的，然后消除了不适当的连接？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损伤后诱导视觉系统连接正常再生。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.