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

• 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
• 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

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。人脑中的神经元数量几乎是非神经元胶质细胞的十分之一，而非神经元胶质细胞为神经元功能提供支持。秀丽隐杆线虫（Caenorhabditis elegans， C. elegans）在保持神经元信号丰富度的同时，降低了细胞的复杂性，使其成为研究E/I平衡的良好模型系统。本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。秀丽隐杆线虫将被用作这方面的模型