The role of central cholinergic pathways in a variety of cognitive behaviors and its role in neurodegenerative diseases has been well documented. It is also recognized nicotine's actions on the brain involves disruption of endogenous cholinergic signaling. In spite of the importance of this signaling pathway, almost nothing is known about the properties of cholinergic transmission at a cellular level. This proposal will establish a model system for the examination of cholinergic transmission and elucidade some fundamental properties of nicotinic transmission in the brain. Transgenic mice expressing GFP or GFP-tau protein under the control of the choline acetyltransferase promoter (ChAT) will be generated. The selective targetting of the transgene to cholinergic neurons in the brain will be determined by immunocytochemical techniques using antibodies against ChAT and GFP. Using the ChAT GFP-tau mice, evoked nAChR responses on interneurons at the stratum radiatum of the hippocampus will be examined by stimulating cholinergic fibers in septo-hippocampal slices using a patch electrode. The effects of acetylcholine esterases on nAChR responses will be examined in order to characterize transmitter diffusion and its ability to act on non-synaptic receptors. Quantal content, probability of release, and number of sites will be determined. Using whole cell voltage-clamp recordings from CA3 pyramidal cells of the hippocampus, the modulation of glutamate release from mossy fiber terminals by synaptically released acetylcholine will be examined. Direct monitoring of ACh release from presynaptic boutons will be monitored using styryl dyes and live cell imaging from acute slices as well as from septal neurons in culture. These studies will be the first detailed examination of cholinergic transmission in the central nervous system and will also provide an invaluable tool to researchers for studying cholinergic processes. The proposal will also begin examining the role of central cholinergic system in mediating nicotine addiction.
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