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: 10054203
• 负责人: Salvatore James Cherra
• 金额: $ 24.31万
• 依托单位: UNIVERSITY OF KENTUCKY
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054203
• 关键词: Affect; Award; Behavior; Behavioral; Biochemical; Biochemistry and Cellular Biology; Biological; Biological Assay; Biological Models; Brain; CRISPR/Cas technology; Caenorhabditis elegans; California; Cells; Cholinergic Receptors; Cholinesterase Inhibitors; Convulsions; Data; Disease; Electron Microscopy; Electrophysiology (science); Environment; Epidermis; Epilepsy; Equilibrium; Faculty; Frequencies; Future; Genes; Genetic; Genetic Screening; Genetic Techniques; 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 mutation; genomic locus; 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。人脑中的神经元数量比非神经元胶质细胞多出近十比一，后者为神经元功能提供支持。在保持神经元信号丰富性的同时，线虫细胞复杂性降低，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来调节 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此模型 该项目的原因如下：1）其神经系统已被完全绘制，2）它已被广泛用于研究神经元网络如何形成和维持，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，并且4）易于通过遗传技术进行操纵。由于这些原因，线虫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：利用电子显微镜和电生理学确定两种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。目标 2：利用遗传、细胞生物学和生化方法阐明维持突触连接的 ZIG-10 信号通路。目标 3：确定新型转运蛋白如何调节体内神经元活动和 E/I 平衡。该提案的完成将使人们更深入地了解神经元和非神经元胶质细胞如何合作调节 E/I 平衡。此外，这项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金一石博士的指导下在加州大学圣地亚哥分校进行。加州大学圣地亚哥分校和一流的神经科学教师为拟议的研究提供了良好的环境，该研究在各自领域的领导者马克·埃利斯曼博士和达尔文·伯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来完成指导阶段提出的研究。通过实践培训以及与埃利斯曼博士和伯格博士的正式会议，我将学习如何使用新技术来剖析神经系统的结构与功能关系。这将使我了解神经元和非神经元细胞如何相互作用以在短期内调节 E/I 平衡。在独立阶段，我将这些新技术与我在分子和细胞生物学方面的专业知识相结合， 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以及在疾病状态下是如何被破坏的。总的来说，该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（包括癫痫、精神分裂症和自闭症谱系）中被破坏。

项目成果

Expanded genetic screening in Caenorhabditis elegans identifies new regulators and an inhibitory role for NAD+ in axon regeneration.

对秀丽隐杆线虫的扩展基因筛查发现了 NAD 在轴突再生中的新调节因子和抑制作用。

• 发表时间: 2018
• 影响因子: 7.7
• 作者: Kim, Kyung Won;Tang, Ngang Heok;Piggott, Christopher A;Andrusiak, Matthew G;Park, Seungmee;Zhu, Ming;Kurup, Naina;Cherra 3rd, Salvatore J;Wu, Zilu;Chisholm, Andrew D;Jin, Yishi
• 通讯作者: Jin, Yishi

PXF-1 promotes synapse development at the neuromuscular junction in Caenorhabditis elegans.

PXF-1 促进秀丽隐杆线虫神经肌肉接头突触的发育。

• 发表时间: 2022
• 作者: Lamb, Reagan;Dhar, Bithika;Cherra 3rd, Salvatore J
• 通讯作者: Cherra 3rd, Salvatore J