Acetylcholine is the most widely distributed neurotransmitter in the nervous system. In the brain, it has been demonstrated to be involved in many higher cognitive functions including learning and memory. Specifically, the involvement of muscarinic cholinergic transmission in learning and memory has been demonstrated in the hippocampus and neocortex. Neurological disorders, such as Alzheimer's Disease, that involve a deficit in memory function are characterized by a loss of cholinergic innervation of the cortex and hippocampus from the basal forebrain. Recently, five muscarinic receptor subtypes (m1-m5) have been identified by molecular cloning techniques and four of those subtypes (m1 -m4) have been localized to the hippocampus utilizing subtype specific antibodies. Several diverse modulatory functions have been attributed to muscarinic receptors in the hippocampus, but their assignment to individual receptor subtypes has been hindered by the lack of specific pharmacological tools to discriminate between subtypes. The following proposed research will use immunocytochemistry, neuroanatomical tracing methods and receptor knockdown strategies to identify the pre- and postsynaptic localization and function of the m4 subtype in defined hippocampal circuits. These studies will further our understanding of the modulatory roles of muscarinic transmission in the hippocampus.
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