Synaptic Transmission: Mechanisms and Modulation

神经处理，无论是触摸热炉子的反射性反应，还是听到悲伤的歌曲时充满情感的回忆，都是由于神经回路的活动，这些神经回路由电激活的神经元组成，在被称为突触的特殊接触部位相互通信。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。我们的研究项目解决了神经传递的基本过程，它的调制，以及突触决定神经回路计算特性的方式。神经传递是一个高度调控的胞吐过程，在这个过程中，含有递质的囊泡与突触前膜融合，释放其内容物。该递质通过短距离的扩散与突触后靶点上的受体结合。神经元之间联系的强度取决于突触后侧受体的密度和突触前侧释放的递质的数量。突触前终末的钙离子浓度控制着融合的小泡的数量，而小泡的数量又决定了递质的释放量。 我们的研究项目使用了各种“模型”突触，选择它们是因为它们具有良好的生理学和解剖学特性，或者是因为它们表现出独特的释放或可塑性。在我们资助的最后一个周期中，我们完成了一系列研究，最终开发了一个被广泛引用的、详细的钙通道和囊泡共同定位的生物物理模型，解释了脊椎动物神经肌肉连接处神经传递的关键特征。我们还比较了青蛙嗅觉受体和主嗅球二尖瓣细胞与副嗅球同源突触之间的基础释放和活动依赖性突触的可塑性。我们展示了这两个系统的感觉到中枢神经元突触的不同活动依赖属性(抑制和促进)如何使它们适应由这些独立的气味处理电路执行的不同感觉接收和处理任务。 在下一个周期中，我们将扩展我们对钙离子通道-囊泡共定位的研究，以探索它们对释放活动依赖的变化(小鼠和青蛙神经肌肉连接)的影响。我们将把我们对鼻子到AOB突触的研究扩展到链中的下一个突触，AOB到杏仁核。这项工作将解决在杏仁外侧核中发现的一种鲜为人知的低频、长期增强形式，这是AOB输出的目标。以前关于小龙虾神经肌肉连接的工作将扩展到囊泡膜再循环的荧光和电子显微镜研究，以解决与突触前终末含有递质的囊泡的“生命周期”相关的基本问题。这延续了我们研究计划的主要主题：从单个突触属性建立功能电路处理能力。 虽然我们的NSERC项目解决了神经元通信的基础科学，但它也对解决实际问题有直接影响。大多数神经和许多神经肌肉疾病是突触传递功能障碍的直接结果，针对传递过程中特定步骤的药物的治疗效果证明了这一点。因此，了解突触传递的过程及其调控，以便开发破译正常大脑功能所需的信息，并合理设计治疗策略来治疗神经疾病，是非常重要的。

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.