Molecular biological and biochemical studies of the members of the nicotinic acetylcholine receptor (nAChR) Family, including those studies supported in the past by this Project, have allowed the discovery of several interesting and unanticipated properties of these prototypical ligand-gated ion channels. Nowhere is this more apparent than in studies of one specific nAChR subtype: the alpha7 nAChR. For example, we now know that the expression of the mRNA encoding a single alpha7 subunit is capable of allowing expression of a fully functional acetylcholine-gated channel, which surprisingly fluxes calcium with a permeability on par with the NMDA receptor. Moreover, we know that the alpha7 receptor is expressed in the hippocampus, a brain region important for memory formation, and that the alpha7 receptor modulates neuronal function in this brain region. Finally, in the last Project Period, we made two discoveries concerning alpha7 receptors that also were surprising. We discovered that hippocampal alpha7 receptors activate the Mitogen-Activated Protein Kinase (MAPK) cascade, the prototypical signal transduction cascade for regulating gene expression and triggering long-term cellular change in the hippocampus. We, along with several other groups, also discovered that the likely causative agent for Alzheimer's Disease, the amyloid beta peptide, is a high-affinity ligand for alpha7 receptors. These latter two discoveries provide the basis for the studies we are proposing for the next Project Period. In the next phase of our studies we will ask the following three questions: 1. Does the alpha7/MAPK pathway regulate the BDNF gene as a target in hippocampal neurons, and is regulation of chromatin structure involved in this process? 2. What are the long-term physiologic consequences of the A-beta peptide interaction with the alpha7 nAChR at hippocampal Schaffer/collateral synapses? 3. What are the behavioral consequences of the A-beta/alpha7 nAChR interaction, studied in vivo using genetically engineered mouse models? These experiments are motivated by our desire to understand the physiologic roles and mechanisms of action of the alpha7 nAChR in the CNS, and to understand its potential contribution to neurological disorders.
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