Acetylcholine acting through muscarinic receptors modulates the excitability of neurons by altering various sodium, calcium, and potassium channels. This modulation of excitability plays a central role in cholinergic regulation of wakefulness, cognition, and memory. The goal of the proposed research is to understand muscarinic changes in action potential formation and firing patterns in terms of modulation of particular ion channels. Patch clamp techniques will be used to study the control of sodium, potassium, calcium channels in sympathetic, hippocampal, and dopamine neurons by muscarinic stimulation. The primary experimental preparation will be acutely isolated neurons, which allow voltage-clamp with sufficient speed to characterize modulation of the large, rapid currents flowing during action potentials. This will extend previous work using brain slices, in which only relatively small and slow currents could be studied under voltage-clamp. We will directly examine currents flowing during action potentials by first recording action potential wave-forms and, in the same cell, using those wave forms as command voltages in voltage clamp experiments. By using pharmacological tools to separate individual current sand performing both current-clamp and voltage-clamp experiments in the presence of acetylcholine, it should be possible to determine the role of modulation of particular channel types in contribution to overall changes in excitability. Muscarinic control of ion channels and neuronal excitability is a basic process for the normal operation of the brain, and evidence suggests changes in the aging brain. Changes in muscarinic modulation of hippocampal neurons may be centrally involved in the symptoms of Alzheimer's disease, and better understanding of the channels involved may lead to novel therapeutic interventions, for example by using ion channel blockers to mimic effects of acetylcholine.
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