Chemical and electrical synapse formation in vivo.

项目描述（由申请人提供）：该项目的长期目标是了解体内调节神经回路和电突触形成的分子途径。神经回路是由突触组织的，突触是粘合和交流的专门场所，其模式和特性构成了所有大脑功能的基础。突触可以是化学的，信号通过神经递质释放和接收传递；也可以是电的，信号直接通过神经元之间的间隙连接传递。其中，化学突触近年来受到了更多的关注；然而，越来越多的证据表明，电突触在大脑中广泛存在，它们调节从感觉知觉到皮层处理再到运动输出的神经回路。潜在的神经回路和突触的形成是确保神经元选择合适的目标和招募复杂的突触机制到接触部位的遗传机制。然而，调控这些过程的基因还没有被很好地理解，特别是关于电突触的形成。该建议将使用斑马鱼毛特纳(M)电路作为理解神经回路布线和电突触形成的遗传基础的模型。表征良好的M电路简单易懂，是典型的逃逸反应行为所必需的。这些特性，再加上专门标记神经回路细胞及其化学和电突触的遗传工具，为研究回路布线和发现影响电突触发生的突变提供了一个独特的机会。该研究的目标是研究M电路连接（Aim1）期间发生的正常发育步骤，确定特异性影响电突触形成的突变，并在细胞生物学和功能水平（Aim2）上研究其缺陷，并确定潜在的突变基因，为构建电突触（Aim3）的分子机制提供第一个见解。鉴于突触发育或功能缺陷与许多神经发育障碍有关，包括自闭症和癫痫，以及与年龄相关的疾病，如阿尔茨海默氏症，这些知识是至关重要的。对突触如何构建的基本理解对于改善疾病的检测和指导治疗的发展是必不可少的。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the molecular pathways that regulate neural circuit and electrical synapse formation in vivo. Neural circuits are organized by synapses, which are specialized sites of adhesion and communication whose patterns and properties form the basis of all of brain function. Synapses can be either chemical, where signals are transmitted via neurotransmitter release and reception, or electrical, where signals pass directly through gap junctions between neurons. Of these, the chemical synapse has received more attention in recent years; however growing evidence suggests that electrical synapses are widespread in the brain where they modulate neural circuits from sensory perception to cortical processing to motor output. Underlying neural circuit and synapse formation are genetic mechanisms ensuring that neurons select appropriate targets and recruit the complex synaptic machinery to the sites of contact. However, the genes that regulate these processes are not well understood, especially in regard to electrical synapse formation. This proposal will use the zebrafish Mauthner (M) circuit as a model for understanding the genetic basis of neural circuit wiring and electrical synapse formation. The well-characterized M circuit is simple and accessible, and is necessary for a stereotypical escape response behavior. These properties, in conjunction with genetic tools that specifically mark the cells of the neural circuit and their stereotyped chemical and electrical synapses, provide a unique opportunity to investigate circuit wiring and to find mutations that affect electrical synaptogenesis. The goal of the research is to investigate the normal developmental steps that occur during M circuit wiring (Aim1), to identify mutations that specifically affect electrical synapse formation and investigate their defects at the cell-biological and functional levels (Aim2), and to identify the underlying mutated genes providing the first insight into the molecular mechanisms that build electrical synapses (Aim3). Such knowledge is critical given that defects in synapse development or function are associated with a number of neurodevelopmental disorders, including autism and epilepsy, and also age-related diseases, such as Alzheimer<s. A fundamental understanding of how synapses are built is essential for improved detection of disease and for guiding the development of therapies.