Molecular Mechanisms of Rapid and Slow Endocytosis

快速和慢速内吞作用的分子机制

• 批准号: 8496135
• 负责人: Kenneth Paradiso
• 金额: $ 23.78万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496135
• 关键词: ATP phosphohydrolase; Action Potentials; Affect; Agrin; Alzheimer' s Disease; Area; Auditory; Axon; Binding; Brain; Brain Stem; Calcium; Calcium Oscillations; Communication; Data; Development; Electric Capacitance; Endocytosis; Exocytosis; Generations; Goals; Grant; Huntington Disease; Kinetics; Knockout Mice; Measurement; Measures; Membrane; Membrane Potentials; Mission; Molecular; Na(+)-K(+)-Exchanging ATPase; National Institute of Neurological Disorders and Stroke; Nerve; Neurons; Ouabain; Parkinson Disease; Pathology; Pharmacology; Phase; Physiological; Potassium Channel; Presynaptic Terminals; Pump; Recovery; Research; Rest; Role; Schizophrenia; Sodium; Staging; Synapses; Synaptic Cleft; Synaptic Transmission; Techniques; Testing; Time; Training; Travel; Work; electrical measurement; information processing; nervous system disorder; neurotransmitter release; patch clamp; postsynaptic; presynaptic; research study; response; uptake

Neuronal communication across the synaptic cleft is fundamental to brain function. The study of synaptic transmission in the brain has largely been limited to postsynaptic patch clamp recordings that provide precise real-time measurements of postsynaptic electrical responses that are used to infer presynaptic activity. A notable exception is the calyx of Held synapse, in the auditory brainstem, which allows direct measurement of electrical activity and neurotransmitter release from the presynaptic terminal. Paired nerve terminal and somatic recordings allow simultaneous measurement of pre- and postsynaptic electrical activity. In addition, presynaptic capacitance recordings can be used to measure changes in membrane area to study the mechanisms of neurotransmitter release (exocytosis) and subsequent membrane uptake (endocytosis). The major aim of the work described here is to better understand currents that are triggered by, and associated with, action potential activity. Particularly, how these currents affect the release of neurotransmitter and subsequent postsynaptic response. Work at the calyx has shown that small currents can travel up the axon a significant distance to inhibit or facilitate action potential generation. Other work has demonstrated that small changes in the presynaptic resting membrane potential can have large effects on the postsynaptic response. This strongly indicates that small currents associated with, or triggered by, action potentials will act to modulate synaptic transmission. The goal of this work is to better understand the mechanisms of these currents, and to determine their role in modulating neurotransmitter release (exocytosis). These studies will be done at an early and later stage of development to determine if the kinetics and the effects of these currents are altered during synapse maturation. This work is consistent with the longstanding commitment of the NINDS to understand basic mechanisms of neuronal function, which is an essential component to understanding how normal physiological function differs from pathological conditions. Accordingly, this research on basic physiological mechanisms of synaptic transmission is a critical component of the mission to reduce the burden of neurological disorders.

通过突触间隙的神经元通信是大脑功能的基础。突触的研究 大脑中的信息传递主要局限于突触后膜片钳记录， 精确的实时测量突触后电反应，用于推断突触前 活动一个值得注意的例外是听觉脑干中的Held突触的萼，它允许直接 测量突触前末梢的电活动和神经递质释放。成对神经 终端和躯体记录允许同时测量突触前和突触后电活动。 此外，突触前电容记录可用于测量膜面积的变化来研究 神经递质释放（胞吐作用）和随后的膜摄取（胞吞作用）的机制。 这里所描述的工作的主要目的是更好地理解电流是由， 与动作电位活动相关。特别是，这些电流如何影响释放 神经递质和随后的突触后反应。对花萼的研究表明， 可以沿着轴突向上行进一段相当长的距离以抑制或促进动作电位的产生。其他工作有 表明突触前静息膜电位的微小变化可以对突触后膜电位产生很大的影响。 突触后反应这有力地表明，与动作相关或由动作触发的小电流 电位将起调节突触传递的作用。这项工作的目标是更好地了解 这些电流的机制，并确定其在调节神经递质释放的作用 （胞吐作用）。这些研究将在开发的早期和后期阶段进行，以确定 这些电流的动力学和作用在突触成熟期间改变。这项工作符合 NINDS长期致力于了解神经元功能的基本机制， 这是理解正常生理功能与病理功能如何不同的一个重要组成部分， 条件因此，对突触传递基本生理机制的研究是一个重要的课题。 减轻神经系统疾病负担的使命的关键组成部分。