Molecular Mechanisms of GABAergic Synapse Modulation by TAFA

TAFA 调节 GABA 能突触的分子机制

• 批准号: 10094258
• 负责人: Sang H Lee
• 金额: $ 38.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094258
• 关键词: Acute; Adult; Affect; Alzheimer' s Disease; Anxiety; Anxiety Disorders; Attention; Bathing; Behavior; Binding; Biochemical; Biochemistry; Biological Assay; Brain; CRISPR/Cas technology; Calcium Channel; Characteristics; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Disinhibition; Electrophysiology (science); Excision; Excitatory Synapse; Extracellular Space; Fright; Functional disorder; Genes; Goals; Hippocampus (Brain); Human; Imaging Techniques; Information Storage; Inhibitory Synapse; Knock-out; Knockout Mice; Knowledge; Ligands; Literature; Maintenance; Mass Spectrum Analysis; Memory; Mental disorders; Mission; Molecular; Mood Disorders; Mus; Neuromodulator; Neurons; Neuropsychology; Outcome; Pharmacology; Physiologic pulse; Play; Process; Protein Family; Proteins; Public Health; Pyramidal Cells; Rattus; Recombinants; Research; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction Pathway; Slice; Social Behavior; Synapses; Synaptic Transmission; System; Techniques; Testing; United States National Institutes of Health; Vesicle; Whole-Cell Recordings; Zebrafish; base; chemokine; chronic pain; classical conditioning; cognitive function; dentate gyrus; disability; experience; experimental study; flexibility; gamma-Aminobutyric Acid; genome editing; hippocampal pyramidal neuron; in vivo; interdisciplinary approach; knock-down; knockout animal; knockout gene; loss of function; member; mossy fiber; nervous system disorder; neural circuit; neuroregulation; new therapeutic target; novel; novel therapeutics; operation; overexpression; presynaptic; receptor; response; synaptogenesis

Project Summary Experience- or use-dependent synapse formation and elimination in neurons are critical for the development and maintenance of neural circuits and information storage. Aberrant control of these processes is thought responsible for numerous neurological and psychiatric diseases. The long-term goal is to better understand the molecular mechanisms by which activity regulates synapse formation and elimination to adjust neural circuit function and behavior. Inhibitory synaptic transmission via GABAergic synapses is critical for shaping network activity and maintaining neural circuit functionality. Defective and aberrant GABAergic synapses are associated with multiple neuropsychological conditions including chronic pain, mood disorders, schizophrenia, and Alzheimer's disease. Like excitatory synapses, inhibitory synapses are highly dynamic and undergo activity- dependent turnover processes not only during early development but also in adult brain. However, molecular mechanisms involved in the regulated elimination of inhibitory synapses are poorly understood. Neuromodulators play important roles in providing flexibility for neural circuit operation and behavior. Although there is a growing body of evidence indicating the important role of neuromodulators in the control of GABA synapses, specific neuromodulator(s) involved in the weakening and elimination of GABAergic synapses remains to be identified. TAFA2 is a brain-specific, novel chemokine-like protein expressed by neurons. Recent studies using TAFA2 gene knockout animals indicate that TAFA2 is involved in anxiety and fear responses. However, molecular mechanisms by which TAFA2 performs its functions in the brain remain unknown. The central hypothesis of this project is that TAFA2 is a novel neuromodulator involved in the activity-dependent elimination of inhibitory synapses. This hypothesis has been formulated based on the preliminary data showing that overexpression and knockdown of TAFA2 had strong effects on the strength and numbers of GABAergic synapses in cultured hippocampal neurons. The objective of the project is thus to characterize and study the function of TAFA2 in the control of GABAergic synaptic transmission and synapse numbers. By using multidisciplinary approaches including biochemistry, advanced imaging techniques, electrophysiology, and CRISPR-Cas9 genome editing, the following three specific aims will be pursued to test the central hypothesis: 1) Examine the rapid modulatory effect of TAFA2 on GABAergic synaptic transmission. 2) Establish TAFA2 function in the elimination of GABAergic synapses in vivo utilizing TAFA2 knockout mice. 3) Investigate mechanisms of TAFA2 action by delineating downstream signal transduction pathway and identifying its receptor candidates. The proposed research is significant, because it is expected to advance and expand the current understanding of the molecular mechanisms involved in the dynamic control of synapse strength and numbers. Moreover, such knowledge ultimately may help to identify new therapeutic targets for neuropsychological disorders.

项目摘要 神经元中经验或使用依赖性突触的形成和消除对于神经元的发育至关重要。 以及维持神经回路和信息存储。这些过程的异常控制被认为是 导致了许多神经和精神疾病。长期目标是更好地了解 活动调节突触形成和消除以调节神经回路的分子机制 功能和行为。GABA能突触的抑制性突触传递是形成网络的关键 活动和维持神经回路功能。缺陷和异常的GABA能突触与 患有多种神经心理疾病，包括慢性疼痛、情绪障碍、精神分裂症， 老年痴呆症像兴奋性突触一样，抑制性突触也是高度动态的， 依赖性周转过程不仅在早期发育过程中，而且在成人脑中也存在。然而，分子 涉及抑制性突触的调节消除的机制知之甚少。 神经调质在为神经回路操作和行为提供灵活性方面起着重要作用。虽然 越来越多的证据表明神经调质在GABA的控制中起着重要作用 突触，参与减弱和消除GABA能突触的特定神经调质 仍有待确认。TAFA 2是一种脑特异性的、由神经元表达的新型趋化因子样蛋白。最近 使用TAFA 2基因敲除动物的研究表明，TAFA 2参与焦虑和恐惧反应。 然而，TAFA 2在大脑中发挥作用的分子机制仍然未知。的 该项目的中心假设是TAFA 2是一种新的神经调节剂，参与活动依赖性的 消除抑制性突触。这一假设是根据初步数据提出的， TAFA 2的过表达和敲低对GABA能的强度和数量有很强的影响， 培养的海马神经元中的突触。因此，该项目的目标是表征和研究 TAFA 2在GABA能突触传递和突触数量控制中的功能。通过使用 多学科方法，包括生物化学，先进的成像技术，电生理学， CRISPR-Cas9基因组编辑，将追求以下三个具体目标来测试中心假设： 1)检查TAFA 2对GABA能突触传递的快速调节作用。2)建立TAFA2 在利用TAFA 2敲除小鼠体内消除GABA能突触中的功能。3)探讨 通过描绘下游信号转导通路并鉴定其作用机制， 受体候选者。拟议的研究意义重大，因为它有望推进和扩大 目前对参与突触强度动态控制的分子机制的理解， 号码此外，这些知识最终可能有助于确定新的治疗靶点， 神经心理障碍