Presynaptic calcium, neurotransmitter release and modulation

神经元通过称为突触的特殊接触部位相互交流。在突触中，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，“突触后”目标可以是另一个神经元、分泌腺或肌肉。这些受体的激活引发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，受突触前末端钙离子（Ca2+）浓度变化的控制。精确控制时间和调节分泌的递质量是神经回路正确处理信息所必需的。为了启动快速，高度调节的释放，Ca2+通过Ca2+通道进入突触前末端，Ca2+通道与含有和释放递质的囊泡紧密共定位。Ca2+内流与囊泡融合之间的密切关系意味着Ca2+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，Ca2+还通过多种生化途径调节传输效果。大多数神经和神经肌肉疾病可以追溯到功能失调的突触传递。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，深入了解突触传递的过程及其调控，对于理解正常的脑功能，合理设计治疗神经系统疾病的治疗策略具有重要意义。我们使用电生理和荧光成像技术的组合，包括Ca2+敏感染料成像和应用蜗牛和蜘蛛毒素阻断Ca2+通道来研究Ca2+内流和释放之间的关系，以确定驱动释放的Ca2+通道的亚型，并阐明神经调节物质（如血清素）和多巴胺通过突触前末端的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.