Nicotinic receptor mediated neurotransmission in the CNS

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The transmission of information between neurons in the brain is governed by the release of chemicals called "neurotranmitters" which bind to ion channels located on the surface of neurons. Cholinergic neurotransmission mediated by neuronal nicotinic acetylcholine receptors plays a fundamental role in enhancing cognitive function such as attention and memory. We do not yet have a clear understanding where exactly these receptors are located in the brain and how precisely they function in mediating communication between neurons. This research program will examine in detail how nicotinic receptors function in the brain using electrophysiology, imaging and genetically engineered mice including a nicotinic gain-of-function mouse line that the applicant has produced. We have also produced mice with fluorescently tagged nicotinic receptors which would allow us to accurately image the receptors on individual neurons. This proposal will examine the function and localization of these receptors in specific neurons in brain regions important for cognition (attention and memory). We will also examine how nicotinic receptor expression are regulated by cellular processes such as phosphorylation by protein kinases. We propose that protein kinase C can modify nicotinic receptors at specific sites to affect either their expression levels, their movement inside the cell or their function. Furthermore, we will also produce novel technologies to advance the study of nicotinic receptors. Using molecular biological approaches we will produce nicotinic receptors bound to a fluorescent protein that is calcium sensitive (GCaMP5G). Since nicotinic receptors are calcium permeable, nicotinic receptors fused to GCaMP5G would allow us to monitor nicotinic receptor activity by imaging instead of performing electrophysiology. This novel technology would greatly enhance the field. Nicotinic receptors are known not only to enhance attention and memory but are also implicated in other brain regions in enhancing sensory perception and reward. This grant examines the basic fundamental role of nicotinic receptors in mediating communication between neurons in the brain.