The long term objective of this ongoing project is to identify and understand the rules for the transduction of information between axon terminals and their targets: the cell body and dendrites of neurons. These experiments use isolated neurons and brain slices from young rats. Our primary objective is to analyze the role of neurotransmitter modulation and spatial distribution on different ion channel types. Understanding the intrgrative role of ion channel types in single cell behavior is a necessary step in identifying the functional significance of molecular mechanisms in neurobiology. With this proposal we request support to study two classes of ionic currents that play key roles in the transduction process: (1) the subthreshold noninactivating sodium current (INap) and (2) the subtypes of high voltage activated calcium current. We will use fluorescent imaging techniques to identify the location of tetrodotoxin-sensitive increases in intracellular sodium (sites of influx through voltage-gated sodium channels). Patch electrode and brain slice techniques will be used to study the modulation of INap by neurotransmitters and the effect of this modulation on integration of excitatory synaptic input in the dendrites. Imaging of calcium ions in acutely dissociated neurons and brain slices will be used to locate pharmacological subtypes of calcium channels over the neuron cell body and dendrites. Pharmacologic blockers will provide an identification of the role of each calcium channel subtype in the various transduction processes mediated by calcium activated potassium currents. Finally, since we know from our previous work that different neurotransmitters selectively block different subtypes of calcium channels, we will investigate the effects of neurotransmitters and their agonists on the regional change in [Ca2+]i as measured by calcium imaging.
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