Tuning of Inhibitory Synaptic Transmission at the Presynaptic Active Zone

突触前活动区抑制性突触传递的调节

• 批准号: 8889057
• 负责人: Richard Guy Held
• 金额: $ 3.52万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889057
• 关键词: Accounting; Action Potentials; Address; Autistic Disorder; Binding; Biochemical; Brain; Cell membrane; Cells; Childhood; Chromosome Deletion; Cognition Disorders; Cognitive deficits; Communication; Complex; Data; Development; Diffuse; Excision; Funding Mechanisms; Genes; Genetic; Genetic study; Goals; Human; Human Genetics; Individual; Inhibitory Synapse; Knock-out; Knockout Mice; Lead; Learning; Light; Mammals; Measures; Mediating; Modeling; Molecular; Molecular Biology; Molecular Machines; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Neurotransmitters; Outcome; Pathway interactions; Probability; Protein Family; Protein Isoforms; Proteins; Publishing; Recruitment Activity; Relative (related person); Rest; Role; Site; Speech; Speed; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; Synaptic Vesicles; Techniques; Testing; Training; Vertebrates; Vesicle; Viral; Work; cognitive function; experience; insight; nervous system disorder; neurotransmission; neurotransmitter release; novel; overexpression; patch clamp; postsynaptic; presynaptic; presynaptic neurons; public health relevance; receptor; research study; synaptic function; tool; transmission process

DESCRIPTION (provided by applicant): Release of neurotransmitters from a presynaptic nerve terminal initiates synaptic transmission, a key form of information transfer between neurons. The presynaptic active zone, a dense protein network that serves as the site of synaptic vesicle fusion, is a unique feature of the presynaptic nerve terminal compared to other secretory pathways. The active zone orchestrates the synaptic vesicle cycle and endows synaptic transmission with incredible speed and precision required for the complex functions the brain fulfills. ELKS is a protein that localizes tightly to the active zone. Published data and our preliminary results suggest that it fulfills several roles in neurotransmitter release. Human genetic studies found ELKS1 to be associated with neurodevelopmental disorders of speech, indicating relevant functions of ELKS in humans. However, the exact functions of mammalian ELKS are unknown and its mechanisms are not understood. The goal of this study is to understand how ELKS, encoded by two genes in vertebrates, functions at the active zone to contribute to its roles in release. We have previously found that deletion of the ELKS2 gene in mice increases the pool of readily releasable synaptic vesicles at inhibitory synapses. In contrast, my preliminary data indicate that ELKS1 may serve opposing roles in inhibitory transmission. These data lead to the hypothesis that ELKS isoforms differentially tune the parameters of neurotransmitter release. To address this hypothesis, I am using a combination of whole-cell patch clamp recordings, molecular biology, and mouse genetic tools. In the first aim, I will determine the mechanisms by which ELKS2 suppresses release. I will pursue rescue experiments in an ELKS2 knock-out to determine which sequences are necessary and sufficient to suppress release. In aim 2, I will ask the question whether ELKS1 fulfills roles similar to ELKS2. Our preliminary data suggest that there may be some divergent roles between ELKS1 and ELKS2, and I will address these roles in newly generated ELKS1 knock-out mice. My third aim rests on the hypothesis that intricate interplay between ELKS1 and ELKS2 fine-tunes release. I will test two specific working models that could account for our preliminary data, and I will consider alternative outcomes. In summary, my work will provide novel insight into how the makeup of active zones controls synaptic transmission, and, ultimately, how molecular deficiencies at the active zone may contribute to neurological disease.

描述（由申请人提供）：神经递质从突触前神经末梢释放，启动突触传递，这是神经元之间信息传递的关键形式。突触前活性区是一个密集的蛋白质网络，作为突触囊泡融合的场所，与其他分泌途径相比，突触前神经末梢是一个独特的特征。活跃区协调突触囊泡周期，赋予突触传递难以置信的速度和精度，这是大脑完成复杂功能所必需的。ELKS是一种紧密定位于活性区域的蛋白质。已公布的数据及