SYNAPSE FORMATION AND REFINEMENT IN THE VISUAL SYSTEM

哺乳动物的视觉系统需要形成精确的电路才能正常工作。这些 神经元回路是在发育过程中通过在数千个神经元之间形成突触连接来组装的 分化的神经元。尽管谷氨酸能突触的形成对脑的正常功能至关重要 视觉系统，对这些突触是如何形成的知之甚少。最近的工作已经开始识别一些 突触形成的早期细胞事件以及启动这一过程的分子信号。尽管财富丰厚 在过去几年发表的关于这个主题的信息中，关于Synapse的一些最基本的问题 编队仍然无人应答。特别是，突触蛋白在轴突和突触中运输的基本机制 突触形成前的树突才刚刚开始被发现。这些机制是如何改变和调节的 在新的哺乳动物突触蛋白的积累过程中，突触仍然是一个谜。定义这些基本内容 运输机制及其调控对于理解突触信号如何改变和引导是至关重要的 突触蛋白向新突触的运输。这项提议的中心目标是研究分子 视皮层神经元之间突触蛋白向新突触的运输和募集机制。我们 建议通过组合技术来直接解决这些问题，这些技术允许我们可视化并集中处理 分离培养的突触形成过程中荧光标记蛋白的运输和募集 视觉皮质神经元。这项建议的具体目标是：(1)确定细胞内信号通路， 调节突触小泡前体的运输，(2)确定细胞内调节 NMDA受体的运输，以及(3)确定突触蛋白的运输是如何改变的 突触信号。 这些实验的结果将是全面理解细胞和分子的关键。 视皮层发育的潜在机制。这些结果还将为我们提供对 弱视的机制，以及可能的治疗方法。更广泛地说，突触的缺陷 形成可能导致许多神经发育障碍，从智力低下，到自闭症，再到 精神分裂症。了解突触形成的细胞和分子机制可能会使我们的 识别、预防和治疗这些发育障碍的能力。

The mammalian visual system requires the proper formation of exquisitely precise circuits to function correctly. These neuronal circuits are assembled during development by the formation of synaptic connections between thousandsof differentiating neurons. Although the formationof glutamatergic synapses is critical for the proper function of the visual system, little is knownabout how these synapses are formed. Recent work has begun to identify some of the early cellular events in synapse formation as well as the molecular signals that initiatethis process. Despite the wealth of information published on this topic in the past few years, some of the most fundamental questions about synapse formation remain unanswered. In particular, the basic mechanisms of transport of synaptic proteins in axons and dendrites before synapse formation havejust begun to be identified. How these mechanisms are altered and regulated during the accumulation of synaptic protein at new mammaliansynapses remains a mystery. Definingthese basic mechanisms of transport and their regulation is critical to understand how synaptogenic signals might alter and direct transport of synaptic proteins to new synapses. The central goal of this proposal is to investigate the molecular mechanisms of the transport and recruitment of synaptic proteins to new synapses between visual cortical neurons. We propose to address these issues directly by combiningtechniques that allow us to visualize and focally manipulatethe transport and recruitment of fluorescently-tagged proteins during synapse formation between dissociated, cultured visual cortical neurons. The specific aims of this proposal are: (1) to identify intracellular signaling pathways that regulate the transport of synaptic vesicle precursors, (2) to identify intracellular signaling pathways that regulate the transport of NMDA receptors, and (3) to determine how transport of synaptic proteins is altered in response to synaptogenic signals. Results from these experiments will be essential for a comprehensive understanding of the cellular and molecular mechanisms underlying the development of the visual cortex. These results will also provide insight into the mechanisms responsible for amblyopia, as well as possible approaches to therapy. More generally, defects in synapse formation are likely to cause many neurodevelopmentaldisorders¿frommental retardation, to autism, to schizophrenia. Understanding the cellular and molecular mechanismsof synapse formation could revolutionize our ability to identify,prevent, and treat these developmental disorders.