Calcium channels in evoked neurotransmitter release at individual synapses and neurological disease

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Synapses between neurons are critical sites of modulation and plasticity, both in health and in disease. We have devised a new way of investigating the events leading up to the release of chemical neurotransmitters at individual synapses. This is based on measuring, with fluorescence microscopy, rapid changes in the concentration of calcium ions, as well as the rate at which small vesicles containing chemical neurotransmitters are discharged. This approach will allow us to investigate how different channels that transmit calcium ions into the terminal control the release of vesicles, how they influence plasticity, and how synapses are influenced by other modulatory neurotransmitters acting upon presynaptic terminals. Moreover, it has recently been established that some inherited cases of migraine, ataxia (incoordination caused by abnormal cerebellar function) and epilepsy are due to mutations of one subtype of calcium channel. We will apply these novel methods to investigate how the desiase-linked mutations affect calcium signals in nerve terminals, and how they affect neurotransmitter release. By making advances at the cutting edge of basic neuroscience relevant to neurological disease this project may point the way to new approaches of treating several disabling neurological diseases caused by intermittent disturbances of synaptic function.