Synaptic transmission: mechanisms and modulation

突触传递：机制和调制

• 批准号: RGPIN-2019-06871
• 负责人: Delaney, Kerry
• 金额: $ 2.04万
• 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: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=716264
• 关键词: Synaptic; transmission; mechanisms; modulation

Our research uses a variety of "model" synapses, chosen for their advantageous physiology, anatomy or distinct release or plasticity properties, to explore neurotransmission and its regulation by activity or neuromodulators. Our NSERC supported studies address fundamental questions of neuronal communication and they have application to practical problems. Precise control of the amount and timing of release is needed for neural circuits to function properly. Changes in connection strength underly many neural processes as simple as adaptation to constant stimuli or complicated as learning and memory and many neurological and neuromuscular disorders are caused by dysfunctional synaptic communication. We therefore need to understand synaptic transmission to decipher normal brain function and to rationally design therapeutic strategies for neurological disorders. Previous NSERC funded work compared activity dependent plasticity of olfactory to mitral cell synapses in the main olfactory bulb (MOB), to plasticity of vomeronasal to accessory OB (AOB). We showed how their particular activity dependent properties (depressing-MOB; facilitating-AOB) adapt them to the different sensory reception and processing tasks performed by these parallel odor-processing circuits. For example, transmission from mitral to AOB synapses is enhanced for >10 seconds after stimulation of one or a few successive presynaptic action potentials making them exceptional integrators of low frequency activity. We will extend this descriptive work in the next cycle by investigating the biochemical mechanism underlying this unique form of long term "facilitation" (so termed because it only requires a few stimuli to induce it). During the last grant cycle we also described potentiation of AOB to amygdala synapses that is distinctive for the long duration of potentiated release (both a PTP >10 mins and LTP, > 1 hour) that is produced by small amount of low frequency stimulation that can induce it (e.g. <1 min at 5 Hz). The next grant cycle will focus on elucidating the mechanisms by which these synapses implement these forms of activity dependent plasticity and how neuromodulation of presynaptic terminal function by muscarinic acetylcholine receptors affects the induction and maintenance of plasticity. Recycling of vesicles after release is essential to maintain transmission during sustained activation. We will extend our previous studies that used fluorescent styryl dyes and electron microscopy to locate recycling vesicles at the crayfish neuromuscular junction through a collaboration with van Veggel (UvIC, chemistry) that will utilize trapping of luminescent nanoparticles during vesicle endocytosis. These studies will address hypotheses pertaining to the pathways by which recycled membrane is turned into functional docked transmitter vesicles, important information to obtain since many neurological (particularly neuromuscular) disorders can be traced to poor vesicle recycling.

我们的研究使用了各种“模型”突触，选择其有利的生理学，解剖学或独特的释放或可塑性特性，探索神经传递及其调节活动或神经调质。我们的NSERC支持的研究解决了神经元通信的基本问题，并将其应用于实际问题。神经回路正常工作需要精确控制释放的量和时间。连接强度的变化是许多神经过程的基础，这些神经过程简单如适应恒定刺激，复杂如学习和记忆，许多神经和神经肌肉疾病是由突触通信功能障碍引起的。因此，我们需要了解突触传递，以破译正常的大脑功能，并合理地设计治疗神经系统疾病的策略。 以前NSERC资助的工作比较了主嗅球（MOB）中嗅觉到二尖瓣细胞突触的活动依赖性可塑性和犁鼻到辅助OB（AOB）的可塑性。我们展示了它们的特定活动依赖特性（压抑MOB;促进AOB）如何使它们适应这些并行气味处理电路所执行的不同感觉接收和处理任务。例如，在刺激一个或几个连续的突触前动作电位后，从二尖瓣到AOB突触的传输增强>10秒，使它们成为低频活动的特殊整合者。在下一个周期中，我们将通过研究这种独特形式的长期“促进”（如此命名是因为它只需要几个刺激来诱导它）的生化机制来扩展这种描述性工作。在最后一个授予周期中，我们还描述了AOB对杏仁核突触的增强作用，其特征在于由少量低频刺激产生的长时间增强释放（PTP >10分钟和LTP> 1小时），所述低频刺激可以诱导它（例如，在5 Hz下<1分钟）。下一个资助周期将集中于阐明这些突触实现这些形式的活动依赖性可塑性的机制，以及毒蕈碱乙酰胆碱受体对突触前末梢功能的神经调节如何影响可塑性的诱导和维持。释放后囊泡的再循环对于在持续激活期间维持传输是必不可少的。 我们将扩展我们以前的研究，使用荧光苯乙烯基染料和电子显微镜，通过与货车Veggel（UvIC，化学），将利用捕获的发光纳米粒子在囊泡内吞作用的合作，以找到回收囊泡在小龙虾神经肌肉接头。这些研究将解决有关的途径，回收膜变成功能对接的递质囊泡，重要的信息，以获得，因为许多神经（特别是神经肌肉）疾病可以追溯到穷人囊泡回收的假设。