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: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=611939
• 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，无论是触摸热炉子时的反射性反应，还是听到悲伤歌曲时充满感情的回忆，都是由于神经回路的活动，这些神经回路由电活动的神经元组成，它们在称为突触的特殊接触部位相互交流。任何电路的计算能力都来自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。我们的研究项目涉及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外过程，在这个过程中，含有递质的囊泡与突触前膜融合并释放它们的内容物。递质扩散一小段距离，与突触后靶标上的受体结合。神经元对之间连接的强度取决于突触后侧受体的密度和突触前侧释放的递质量。突触前末端的Ca2+离子浓度控制融合囊泡的数量，而融合囊泡的数量又决定了释放的递质量。