Understanding the molecular mechanisms that maintain excitation-inhibition balance in neural circuits

许多神经系统疾病与兴奋性和抑制性（E/I）神经元信号传导之间的不平衡有关。神经系统通常通过调节神经元之间突触连接的数量或强度来维持E/I平衡。人类大脑中的神经元数量几乎是非神经元胶质细胞的十倍，后者为神经元功能提供支持。在保持丰富的神经元信号传导的同时，线虫秀丽隐杆线虫（C. elegans），使其成为研究E/I平衡的一个很好的模型系统。这个提议的总体目标是阐明非神经元细胞和神经元如何相互作用以调节E/I平衡。通过了解神经胶质细胞和神经元如何相互作用，该项目将为癫痫、自闭症谱系或精神分裂症等神经系统疾病的治疗和管理提供新的见解。C.秀丽隐杆线虫将被用作这方面的模型 该项目的主要原因如下：1）它的神经系统已经被完全绘制出来; 2）它被广泛用于研究神经网络是如何形成和维持的; 3）调节神经系统功能的基因和分子机制在人类中是保守的; 4）它很容易通过遗传技术进行操纵。基于这些原因，C. elegans提供了一个简单的模型来研究与E/I失衡相关的神经系统疾病的分子机制。本研究的目标将通过以下具体目标来实现：目标1：确定两个免疫球蛋白结构域跨膜蛋白，ZIG-10，如何调节吞噬途径，以平衡兴奋性和抑制性神经传递，使用电子显微镜和电生理学。目的2：通过遗传学、细胞生物学和生物化学方法阐明ZIG-10信号通路在维持突触连接中的作用。目的3：确定一种新的转运蛋白如何在体内调节神经元活性和E/I平衡。这项提案的完成将提供一个更深入的了解神经元和非神经胶质细胞如何合作，以调节E/I平衡。此外，本研究将揭示影响与神经系统疾病相关的异常神经元活动的机制。最后，该项目将确定自闭症谱系障碍，癫痫，精神分裂症和相关神经系统疾病的新疗法的潜在治疗靶点。 该奖项的指导部分将在加州圣地亚哥大学进行，由Yishi Jin博士指导。加州大学圣地亚哥分校和一流的神经科学系为拟议的研究提供了一个良好的环境，该研究在各自领域的领导者Mark Ellisman博士和达尔文贝格博士的指导下采用了电子显微镜和电生理学。金博士是世界著名的遗传学家和神经生物学家，他将提供资源和指导，以完成在指导阶段提出的研究。通过与Ellisman博士和贝格博士的实际操作培训和正式会议，我将学习如何使用新技术来剖析神经系统的结构-功能关系。这将使我了解神经元和非神经元细胞如何相互作用，以调节短期内的E/I平衡。在独立阶段，运用我在分子和细胞生物学方面的专业知识， 生物化学将使我能够破译E/I平衡在正常状态下是如何调节的，在疾病状态下是如何破坏的。总的来说，在这个奖项期间提出的研究和职业发展将使我能够揭示调节E/I平衡的机制，这种平衡在许多神经系统疾病中被破坏，包括癫痫，精神分裂症和自闭症谱系。

Many neurological disorders are associated with an imbalance between excitatory and inhibitory (E/I) neuronal signaling. The nervous system normally maintains an E/I balance by regulating the number or strength of synaptic connections between neurons. Neurons in the human brain are outnumbered nearly ten to one by non-neuronal glial cells, which provide support for neuronal function. While maintaining the richness of neuronal signaling, the reduced cellular complexity of the roundworm, Caenorhabditis elegans (C. elegans), makes it an excellent model system to study E/I balance. The overall goal of this proposal is to elucidate how non-neuronal cells and neurons interact to regulate E/I balance. By understanding how glial cells and neurons interact, this project will provide novel insights into the treatment and management of neurological disorders such as epilepsy, autism spectrum, or schizophrenia. C. elegans will be used as a model for this project for the following reasons: 1) its nervous system has been fully mapped, 2) it's been widely used to study how neuronal networks are formed and maintained, 3) the genes and molecular mechanisms that regulate nervous system function are conserved with humans, and 4) it is easy to manipulate through genetic techniques. For these reasons, C. elegans provides a simple model to study the molecular mechanisms that underlie neurological disorders associated with E/I imbalance. The goals of this study will be accomplished through the following specific aims: Aim 1: Determine how the two immunoglobulin domain transmembrane protein, ZIG-10, regulates the phagocytosis pathway to balance excitatory and inhibitory neurotransmission using electron microscopy and electrophysiology. Aim 2: Elucidate the ZIG-10 signaling pathway in maintaining synaptic connections using genetic, cell biologic, and biochemical approaches. Aim 3: Determine how a novel transporter regulates neuronal activity and E/I balance in vivo. The completion of this proposal will provide a deeper understanding of how neurons and non-neuronal glia cooperate to regulate E/I balance. Additionally, this study will uncover the mechanism(s) affecting aberrant neuronal activity associated with neurological disorders. Finally, this project will identify potential therapeutic targets for novel treatments of autism spectrum disorders, epilepsy, schizophrenia, and related neurological diseases. The mentored portion of this award will take place at the University of California San Diego under the mentorship of Dr. Yishi Jin. UCSD and the superb neuroscience faculty provide an excellent environment for the proposed research, which employs electron microscopy and electrophysiology under the guidance of Dr. Mark Ellisman and Dr. Darwin Berg, leaders in their respective fields. Dr. Jin, a world-renowned geneticist and neurobiologist, will provide both the resources and guidance to accomplish the research proposed during the mentored phase. Through hands-on training and formal meetings with Dr. Ellisman and Dr. Berg, I will learn how to use new techniques to dissect the structure-function relationship of the nervous system. This will allow me to understand how neurons and non-neuronal cells interact to regulate E/I balance in the short-term. During the independent phase, applying these new techniques with my expertise in molecular and cellular biology and biochemistry will allow me to decipher how the E/I balance is regulated during normal and disrupted during disease states. Overall the research and career development proposed during this award will enable me to uncover the mechanisms that regulate E/I balance that is disrupted in many neurological disorders including epilepsy, schizophrenia, and autism spectrum.