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

了解维持神经回路兴奋抑制平衡的分子机制

基本信息

批准号：
9164281
负责人：
Salvatore James Cherra
金额：
$ 9.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9164281
关键词：
Affect Autistic Disorder Award Behavior Behavioral Biochemical Biochemistry Biological Assay Biological Models Brain Caenorhabditis elegans California Cells Cholinergic Receptors Cholinesterase Inhibitors Clustered Regularly Interspaced Short Palindromic Repeats Convulsions Data Disease Electron Microscopy Electrophysiology (science)Environment Epidermis Epilepsy Equilibrium Faculty Frequencies Future Genes Genetic Genetic Screening Genetic Techniques Genomics Glutamates Goals Human Immunoglobulin Domain Immunoglobulins In Vitro Integral Membrane Protein Investigation Laboratories Learning Mammals Maps Mediating Mentors Mentorship Modeling Molecular Molecular and Cellular Biology Mutation Nematoda Nervous System Physiology Nervous system structure Neuroglia Neurons Neurosciences Neurotransmitters Pathway interactions Patients Phagocytosis Phase Phenotype Physiological Process Protein Binding Domain Proteins RNA interference screen Regulation Research Resistance Resources Schizophrenia Seizures Signal Pathway Signal Transduction Singlet Oxygen Structure-Activity Relationship Symptoms Synapses System Techniques Testing Training Universities Use of New Techniques autism spectrum disorder career development cholinergic density gain of function gain of function mutation in vivo insight meetings member mutant nervous system disorder neural circuit neurotransmission new therapeutic target novel research and development synaptic function synaptogenesis transmission process

项目摘要

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.

许多神经系统疾病与兴奋性和抑制性（E/I）神经元信号之间的失衡有关。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保持E/I平衡。人脑中的神经元被非神经胶质神经胶质细胞的数量超过十比1，这为神经元功能提供了支持。在维持神经元信号的丰富性的同时，round虫的细胞复杂性降低了秀丽隐杆线虫（C. elegans），使其成为研究E/I平衡的绝佳模型系统。该提案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。秀丽隐杆线虫将被用作这一模型由于以下原因：1）其神经系统已被充分映射，2）已广泛用于研究神经元网络如何形成和维护，3）3）调节神经系统功能的基因和分子机制与人类保持了保守，4）它可以通过遗传技术易于操纵。由于这些原因，秀丽隐杆线虫提供了一个简单的模型来研究与E/I不平衡相关的神经系统疾病的分子机制。这项研究的目标将通过以下特定目的来实现：目标1：确定两个免疫球蛋白结构域的跨膜蛋白Zig-10如何调节吞噬作用途径，以平衡使用电子显微镜和电生理学的兴奋性和抑制性神经传递。 AIM 2：阐明使用遗传，细胞生物学和生化方法维持突触连接的ZIG-10信号通路。 AIM 3：确定新型转运蛋白如何调节神经元活性并在体内平衡E/I。该提案的完成将对神经元和非神经胶质神经胶质的合作如何调节E/I平衡进行更深入的了解。此外，这项研究将发现影响与神经系统疾病相关的异常神经活性的机制。最后，该项目将确定自闭症谱系疾病，癫痫，精神分裂症和相关神经疾病的新型治疗靶标的潜在治疗靶标。该奖项的指导部分将在加州大学圣地亚哥分校的指导下举行。 UCSD和出色的神经科学教师为拟议的研究提供了一个极好的环境，该研究在其各自领域的领导者Mark Ellisman博士和Darwin Berg博士的指导下采用了电子显微镜和电生理学。世界知名的遗传学家和神经生物学家金博士将提供在指导阶段完成提出的研究的资源和指导。通过与Ellisman博士和Berg博士的实践培训和正式会议，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。这将使我能够了解神经元和非神经元细胞如何相互作用以调节E/I短期平衡。在独立阶段，将这些新技术应用于我在分子和细胞生物学方面的专业知识以及生物化学将使我能够破译在正常情况下如何调节E/I平衡，并在疾病状态下受到破坏。总体而言，该奖项期间提出的研究和职业发展将使我能够发现调节E/I平衡的机制，这些机制在包括癫痫，精神分裂症和自闭症谱系在内的许多神经系统疾病中受到破坏。