Synaptic Transmission: Mechanisms and Modulation

突触传递：机制和调制

• 批准号: RGPIN-2014-05950
• 负责人: Delaney, Kerry
• 金额: $ 3.57万
• 依托单位: University of Victoria
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=588716
• 关键词: Synaptic; Transmission; Mechanisms; Modulation

Neural processing, be it reflexive responses to touching a hot stove or the emotionally charged recollection of a memory upon hearing a sad song, is due to the activity of neural circuits comprised of electrically active neurons that communicate with each other at specialized sites of contact called synapses. The computational capabilities of any circuit arise from the intrinsic electrical properties of the neurons, their pattern of connectivity and the properties of synapses that connect them. Our research program addresses the fundamental processes of neurotransmission, it's modulation and the ways in which synapses determine the computational properties of neural circuits. Neurotransmission is a highly regulated exocytotic process in which transmitter-containing vesicles fuse with the presynaptic membrane to release their contents. The transmitter diffuses a short distance to bind to receptors on the postsynaptic target. The strength of the connection between the neuronal pair depends on the density of receptors on the postsynaptic side and the amount of transmitter that is released from the presynaptic side. Ca2+ ion concentration in the presynaptic terminal controls the number of vesicles that fuse which in turn determines the amount of transmitter released. Our research program uses a variety of "model" synapses chosen for their advantageous physiology and anatomy or because they exhibit distinct release or plastic properties. During the last cycle of our funding we completed a series of studies culminating in the development of a well-cited, detailed biophysical model of calcium channel and vesicle co-localization that explains key features of neurotransmission at a vertebrate neuromuscular junction. We also compared the basal release and activity dependent plasticity of synapses between frog olfactory receptors and mitral cells in the main olfactory bulb to the homologous synapse in the accessory olfactory bulb (AOB). We demonstrated how the different activity dependent properties (depressing vs. facilitating) of the sensory-to-central neuron synapses of these two systems adapt them to the different sensory reception and processing tasks that are performed by these separate odour-processing circuits. During the next cycle we will extend our work on Ca2+ channel-vesicle co-localization to explore their effects on activity dependent changes in release (mouse and frog neuromuscular junction). We will extend our studies on the nose-to-AOB synapses to the next synapse in the chain, the AOB-to-amygdala. The work will address a poorly understood form of low frequency, long-term potentiation found in the lateral amygdala, which is the target of the AOB's output. Previous work on crayfish neuromuscular junction will be extended with fluorescence and electron microscopic studies of vesicle membrane recycling to address fundamental questions relating to the "life-cycle" of transmitter-containing vesicles in the presynaptic terminal. This continues the main theme of our research program; the building up of functional circuit processing capabilities from individual synaptic properties. While our NSERC program addresses the basic science of neuronal communication it also has direct implication for addressing practical issues. The majority of neurological and many neuromuscular disorders are the direct result of ddirect result of dysfunctional synaptic transmission as evidenced by the therapeutic effect of drugs that target specific steps in the transmission process. It is therefore important to understand the processes of synaptic transmission and their regulation in order to develop the information needed to decipher normal brain function and to rationally design therapeutic strategies to treat neurological disorders.

神经处理，无论是对触摸热炉子的反射反应，还是听到悲伤歌曲时对记忆的情绪化回忆，都是由于神经回路的活动，这些神经回路由电活性神经元组成，这些神经元在称为突触的专门接触部位相互通信。 任何电路的计算能力都源于神经元的内在电特性、它们的连接模式以及连接它们的突触的特性。 我们的研究计划涉及神经传递的基本过程，它的调制和突触决定神经回路的计算特性的方式。 神经传递是一个高度调节的胞吐过程，其中含有递质的囊泡与突触前膜融合以释放其内容物。递质扩散一小段距离后与突触后靶点上的受体结合。 神经元对之间连接的强度取决于突触后侧受体的密度和从突触前侧释放的递质的量。突触前末梢中的Ca 2+离子浓度控制融合的囊泡数量，而融合的囊泡数量又决定释放的递质量。 我们的研究计划使用了各种各样的“模型”突触，选择这些突触是因为它们具有优越的生理学和解剖学特性，或者因为它们表现出独特的释放或塑性特性。在我们的资助的最后一个周期，我们完成了一系列的研究，最终在一个良好的引用，详细的钙通道和囊泡共定位的生物物理模型的发展，解释了在脊椎动物神经肌肉接头的神经传递的关键特征。我们还比较了青蛙嗅觉受体和僧帽细胞之间的突触的基础释放和活动依赖的可塑性在主嗅球的同源突触在副嗅球（AOB）。我们展示了这两个系统的感觉-中枢神经元突触的不同活动依赖特性（抑制与促进）如何使它们适应这些独立的气味处理回路所执行的不同感觉接收和处理任务。 在下一个周期中，我们将扩展我们的工作对Ca 2+通道囊泡共定位，以探索其对释放（小鼠和青蛙神经肌肉接头）的活动依赖性变化的影响。我们将把我们对鼻子-AOB突触的研究扩展到下一个突触，即AOB-杏仁核。 这项工作将解决一个知之甚少的形式，低频，长时程增强发现在外侧杏仁核，这是目标的AOB的输出。 小龙虾神经肌肉接头的荧光和电子显微镜研究囊泡膜回收，以解决有关的“生命周期”的发射器包含囊泡在突触前终端的基本问题将延长以前的工作。这延续了我们研究计划的主题;从个体突触特性建立功能电路处理能力。 虽然我们的NSERC计划涉及神经元通信的基础科学，但它也直接涉及解决实际问题。大多数神经系统疾病和许多神经肌肉疾病是突触传递功能障碍的直接结果，这一点可以通过靶向传递过程中特定步骤的药物的治疗效果来证明。因此，重要的是要了解突触传递的过程及其调节，以开发所需的信息来破译正常的大脑功能，并合理地设计治疗策略来治疗神经系统疾病。