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 神经元回路在发育过程中通过数千个神经元之间的突触连接的形成来组装， 分化神经元。尽管突触的形成对神经元的正常功能至关重要， 视觉系统中，我们对这些突触是如何形成的知之甚少。最近的工作已经开始确定一些 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 在过去的几年里，关于这个主题发表的信息中，关于突触的一些最基本的问题 编队仍然无人应答。特别是，突触蛋白在轴突中转运的基本机制， 突触形成前的树突才刚刚开始被识别。这些机制是如何改变和调节的 突触蛋白在新突触中的积累过程仍然是一个谜。定义这些基本 转运机制及其调节对于理解突触发生信号如何改变和引导 突触蛋白质向新突触的转运。该提案的中心目标是研究分子 视皮层神经元之间突触蛋白的运输和募集机制。我们 我建议通过结合技术直接解决这些问题，这些技术使我们能够可视化并集中处理这些问题。 在突触形成期间，分离的、培养的、 视皮层神经元本研究的具体目标是：（1）确定细胞内信号通路， 调节突触囊泡前体的转运，（2）确定调节突触囊泡前体的细胞内信号通路， NMDA受体的转运，以及（3）确定突触蛋白的转运如何响应于 突触信号 这些实验的结果对于全面了解细胞和分子生物学的作用是必不可少的。 视觉皮层发育的潜在机制。这些结果也将提供深入了解 弱视的机制，以及可能的治疗方法。更普遍的是，突触缺陷 可能导致许多神经发育障碍从智力迟钝到自闭症， 精神分裂症了解突触形成的细胞和分子机制可以彻底改变我们的 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 developmentby 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 pathwaysthat 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 neurodevelopmentaldisordersfrommental 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.