SYNAPSE FORMATION AND REFINEMENT IN THE VISUAL SYSTEM

描述(申请人提供)：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在数千个分化的神经元之间形成突触连接来组装。虽然谷氨酸能突触的形成对视觉系统的正常功能至关重要，但人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识别突触形成过程中的一些早期细胞事件以及启动这一过程的分子信号。尽管在过去的几年里发表了关于这一主题的大量信息，但关于突触形成的一些最基本的问题仍然没有得到回答。特别是，突触蛋白在突触形成之前在轴突和树突中运输的基本机制才刚刚开始被识别。在新的哺乳动物突触积累突触蛋白的过程中，这些机制是如何改变和调节的仍然是一个谜。确定这些基本的运输机制及其调控对于理解突触产生的信号如何改变以及将突触蛋白直接运输到新的突触至关重要。这一建议的中心目标是研究视皮层神经元之间突触蛋白向新突触的运输和募集的分子机制。我们建议通过结合技术来直接解决这些问题，这些技术允许我们可视化和集中地操纵在分离的培养的视觉皮质神经元之间形成突触期间荧光标记蛋白的运输和招募。这一建议的具体目的是：(1)确定调节突触小泡前体运输的细胞内信号通路；(2)确定调节NMDA受体运输的细胞内信号通路；(3)确定突触蛋白的运输是如何响应突触信号的。这些实验的结果对于全面理解视皮层发育的细胞和分子机制至关重要。这些结果还将为弱视的机制以及可能的治疗方法提供深入的见解。更广泛地说，突触形成的缺陷可能会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以彻底改变我们识别、预防和治疗这些发育障碍的能力。

DESCRIPTION (provided by applicant): 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 thousands of differentiating neurons. Although the formation of glutamatergic synapses is critical for the proper function of the visual system, little is known about 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 initiate this 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 have just begun to be identified. How these mechanisms are altered and regulated during the accumulation of synaptic protein at new mammalian synapses remains a mystery. Defining these 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 combining techniques that allow us to visualize and focally manipulate the 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 neurodevelopmental disorders from mental retardation, to autism, to schizophrenia. Understanding the cellular and molecular mechanisms of synapse formation could revolutionize our ability to identify, prevent, and treat these developmental disorders.