Presynaptic calcium, neurotransmitter release and modulation

神经元在称为突触的特殊接触部位相互通信。在突触，一种神经递质物质从“突触前”神经元分泌出来，并扩散一小段距离，与“突触后”目标上的受体结合，目标可以是另一个神经元、分泌腺或肌肉。这些受体的激活启动了构成神经元间信号的电和/或生化事件。递质释放是一个高度调控的过程，受突触前终末钙离子浓度的变化控制。神经回路需要精确地控制时间和调节分泌的递质数量，才能正确处理信息。为了启动快速、高度调节的释放，Ca~(2+)通过与含有和释放递质的小泡紧密共存的Ca~(2+)通道进入突触前终端。Ca~(2+)内流与囊泡融合的密切关系表明，Ca~(2+)通道调节是调节突触连接强度的有效途径。除了直接驱动囊泡融合外，钙离子还通过各种生化途径来调节传递的效果。大多数神经和神经肌肉疾病可以追溯到突触传递功能障碍。在许多情况下，神经功能的正常调节，如对持续刺激或短期和长期学习和记忆的适应，是由突触连接强度的变化引起的。因此，非常详细地了解突触传递的过程及其调控，对于了解正常的大脑功能和合理设计治疗策略来治疗神经疾病是非常重要的。我们结合电生理和荧光成像技术，包括钙敏感染料成像和应用蜗牛和蜘蛛毒素阻断钙通道来研究钙内流和释放之间的关系，确定驱动释放的钙通道亚型，并阐明神经调节物质如5-羟色胺和多巴胺通过突触前终末受体调节释放的机制。

Neurons communicate with each other at specialized sites of contact called synapses. At synapses a neurotransmitter substances is secreted from the "preysnaptic" neuron and diffuses a short distance to bind to receptors on the "postsynaptic" target, which can be another neuron, a secretory gland or a muscle. Activation of these receptors initiates electrical and/or biochemical events that constitute the inter-neuronal signal. Transmitter release is a highly regulated process that is controlled by changes in calcium ion (Ca2+) concentration in the presynaptic terminal. Precise control of the timing and regulation of the amount of transmitter that is secreted is needed for neural circuits to process information properly. To initiate rapid, highly regulated release, Ca2+ enters the presynaptic terminal through Ca2+ channels that are tightly colocalized with vesicles that contain and release the transmitter. The intimate relationship between Ca2+ influx and vesicle fusion means that Ca2+ channel regulation is an effective way to modulate synaptic connection strength. As well as driving vesicle fusion directly, Ca2+ acts through a variety of biochemical pathways to modulate the efficacy of transmission. The majority of neurological and neuromuscular disorders can be traced to dysfunctional synaptic transmission. In many cases normal modulation of neural function such as adaptation to constant stimuli or short and long-term learning and memory are caused by changes in synaptic connection strength. It is therefore important to understand in great detail the processes of synaptic transmission and their regulation in order to understand normal brain function and to rationally design therapeutic strategies to treat neurological disorders. We use a combination of electrophysiological and fluorescence imaging techniques, including imaging of Ca2+ sensitive dyes and applying snail and spider toxins to block Ca2+ channels to study the relationship between Ca2+ influx and release, to determine the sub-types of Ca2+ channels that are driving release and to elucidate the mechanisms whereby neuromodulatory substances such as serotonin, and dopamine regulate release through receptors on presynaptic terminals.