Synaptic transmission: mechanisms and modulation

我们的研究使用了各种“模型”突触，这些突触因其优越的生理学、解剖学或独特的释放或可塑性特性而被选中，以探索神经传递及其活动或神经调节剂对其的调节。我们的NSERC支持的研究解决了神经元通信的基本问题，它们适用于实际问题。神经回路需要精确控制释放的数量和时间，才能正常工作。许多神经过程，如对持续刺激的适应，或复杂的学习和记忆，以及许多神经和神经肌肉疾病，都是由突触通讯功能障碍引起的。因此，我们需要了解突触传递来破译正常的大脑功能，并合理地设计神经疾病的治疗策略。*以前由NSERC资助的工作比较了主嗅球(MOB)中嗅觉与二尖瓣细胞突触活动相关的可塑性，以及犁鼻与副OB(AOB)之间的可塑性。我们展示了它们特定的活动依赖属性(抑制-MOB；促进-AOB)如何使它们适应由这些并行气味处理电路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突触的传递在10秒内得到增强，使它们成为低频活动的特殊积分者。我们将在下一个周期扩展这一描述性工作，研究这种独特的长期“促进”形式(之所以这样命名，因为它只需要几个刺激就能诱导它)背后的生化机制。在上一个授予周期中，我们还描述了AOB对杏仁核突触的增强作用，这种增强作用在长时间的增强释放(包括PTP和GT；10分钟和LTP；1小时)方面是独特的，这是由可以诱导它的少量低频刺激(例如，5赫兹的1分钟)产生的。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，以及毒碱样乙酰胆碱受体对突触前终末功能的神经调节如何影响可塑性的诱导和维持。释放后的囊泡循环对于维持持续激活过程中的传递至关重要。我们将扩展我们之前的研究，通过与van Vegel(UVic，化学)的合作，使用荧光苯乙烯染料和电子显微镜来定位小龙虾神经肌肉连接处的回收小泡，这将利用在小泡内吞过程中捕获发光纳米颗粒。这些研究将解决与回收膜转化为功能对接的递质囊泡的途径有关的假说，这是需要获得的重要信息，因为许多神经(特别是神经肌肉)疾病可以追溯到囊泡循环不良。

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.**