The regulation of synaptic transmission and neural circuit function

突触传递和神经回路功能的调节

• 批准号: 9358606
• 负责人: Wei Lu
• 金额: $ 171.87万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9358606
• 关键词: AMPA Receptors; Alzheimer' s Disease; Animal Behavior; Autistic Disorder; Behavioral; Behavioral Genetics; Binding Proteins; Biochemical; Cell Adhesion Molecules; Cells; Communication; Development; Electrophysiology (science); Glutamate Receptor; Glutamates; Goals; Inhibitory Synapse; Learning; Manuscripts; Membrane Proteins; Memory; Mental Depression; Mental disorders; Midbrain structure; Molecular; Motivation; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; National Institute of Neurological Disorders and Stroke; National Institute on Alcohol Abuse and Alcoholism; Nature; Neurons; Pathogenesis; Peer Review; Play; Population; Preparation; Process; Proteins; Publishing; Regulation; Reporting; Research; Role; Series; Synapses; Synaptic Transmission; Synaptic plasticity; United States National Institutes of Health; Veronica; Work; dopaminergic neuron; insight; interest; nervous system disorder; neural circuit; neuromechanism; neuronal circuitry; novel; protein protein interaction; relating to nervous system; research study; synaptogenesis; trafficking

The lab is interested in understanding molecular and cellular mechanisms underlying synapse formation and synaptic plasticity, and in the long term elucidating synaptic mechanisms underlying neuronal circuit function in animal behavior. We believe that these studies will provide fundamental insights into neural underpinnings for learning and memory, and will identify synaptic and neural circuit malfunctions that are involved in many neurological and mental disorders, such as Alzheimer's disease, depression and autism. Specifically, during the 2016 fiscal year, we have made following progress: For research Aim 1: we have successfully determined the role of GSG1L, a tetraspanning protein that binds to AMPARs, in the regulation of excitatory synaptic strength and animal behavior. Currently a manuscript for this work has been published in Nature Communications and another manuscript is under revision. In addition, we have made substantial progress in determining the role of FRRS1L, a novel and unexplored membrane protein in the regulation of AMPA receptor trafficking and function. For research Aim 2, we have identified two novel proteins interacting with NMDA receptors. Currently we have made substantial progress in determining the function of one of the two protein-protein interactions in the regulation of excitatory synaptic transmission and synaptic plasticity. For research Aim 3: we have revealed several key molecular processes that are critical for the development of inhibitory synapses. We found that activities of glutamate receptors in developing neurons are crucial for inhibitory synapse development. Current a manuscript for this work has been published in Cell reports. In addition, we have determined the role of cell adhesion molecules in the regulation of inhibitory synapse development. Currently, a manuscript for this work is under preparation. For research Aim 4, we have completed series of behavioral experiments in the mutant mice in which the majority of glutamatergic input onto midbrain dopamine neurons has been genetically inactivated. These experiments demonstrate that glutamatergic input onto dopamine neurons plays a specific and prominent role in behavioral processes that require high-level motivation. Currently, a manuscript about this work has been submitted for peer review. Finally, during the 2016 fiscal year, we have collaborated with Dr. Katherine Roche group at NINDS, NIH to study the function of diseased-associated mutations in NMDA receptors. In addition, we collaborated with Dr. Veronica Alvarez lab at NIAAA, NIH and Dr. Thomas Hnasko lab at UCSD to study the mutant mice lacking glutamatergic input onto dopamine neurons.

该实验室有兴趣了解突触形成和突触可塑性的分子和细胞机制，以及在长期阐明动物行为中神经元电路功能的突触机制中。我们认为，这些研究将为学习和记忆的神经基础提供基本见解，并将确定与许多神经系统和精神障碍有关的突触和神经回路故障，例如阿尔茨海默氏病，抑郁症和自闭症。具体来说，在2016财政年度，我们已经取得了遵循： 对于研究目的1：我们成功地确定了与AMPAR结合的四个蛋白质GSG1L的作用，在调节兴奋性突触强度和动物行为中。目前，这项工作的手稿已在《自然通讯》中发表，另一份手稿正在修订中。此外，我们在确定FRRS1L的作用方面取得了重大进展，FRRS1L是一种新颖且未开发的膜蛋白在AMPA受体运输和功能调节中的作用。 对于研究目标2，我们已经确定了两种与NMDA受体相互作用的新型蛋白质。目前，我们在确定两种蛋白质蛋白质相互作用之一在调节兴奋性突触传播和突触可塑性中的功能方面取得了重大进展。 对于研究目的3：我们揭示了几个关键分子过程，这对于抑制突触的发展至关重要。我们发现，谷氨酸受体在发育神经元中的活性对于抑制突触发育至关重要。目前，这项工作的手稿已发表在细胞报告中。此外，我们确定了细胞粘附分子在调节抑制突触发育中的作用。目前，这项工作的手稿正在准备中。 对于研究目的4，我们已经完成了突变小鼠中的一系列行为实验，其中大多数谷氨酸能在中脑多巴胺神经元上输入已被遗传灭活。这些实验表明，谷氨酸能对多巴胺神经元的输入在需要高级动机的行为过程中起着特定而突出的作用。目前，已经提交了有关这项工作的手稿进行同行评审。 最后，在2016财政年度，我们与NIHS NIH的Katherine Roche Group博士合作研究了NMDA受体中患病相关突变的功能。此外，我们与NIAAA，NIH的Veronica Alvarez Lab博士和UCSD的Thomas Hnasko Lab博士合作研究了在多巴胺神经元上缺乏谷氨酸能输入的突变小鼠。