Presynaptic calcium, neurotransmitter release and modulation

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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.