The hippocampus is a key cortical structure that plays an important role in a number of normal physiological process including formation of short- and long-term memory, and is a primary site of pathology in several common neurological disorders including Alzheimer's disease. Muscarinic acetylcholine receptors (mAChRs) play a number of physiological roles in the hippocampus and are likely to be important for normal cognitive function. Determination of the specific roles of each of the mAChR subtypes in regulating hippocampal function will be critical for developing a detailed understanding of the roles of mAChRs in both normal and pathological hippocampal function. Recent advances in development of pharmacological probes for specific mAChRs, makes it possible to definitively determine the function of the m1 mAChR subtype. A series of studies is proposed that is aimed at determining the role the m1 mAChR plays in regulating hippocampal function. We will employ patch clamp techniques and field recordings, together with subtype-specific mAChR toxins, subtype specific antibodies, and newly developed pharmacological reagents to test the hypothesis that the m1 mAChR mediates the cholinergic-induced potentiation of NMDA receptor currents and the facilitation of LTP induction. Also, we will test the hypothesis that these effects of exogenously applied agonists can be mimicked by the release of synaptic acetylcholine.
