The most abundant and ubiquitous excitatory neurotransmitters in the CNS - - glutamate (Glu), aspartate (Asp) and acetylcholine (ACh) -- have vitally important beneficial functions, including the facilitation of cognition and memory, but also harbor treacherous neurotoxic potential. This neurotoxic potential is generally referred to as """"""""excitotoxicity"""""""". However, in addition to classical excitotoxicity, several new mechanisms have now been discovered by which excitatory transmitter neurotoxicity can occur. In this project, the applicants will focus both on classical excitotoxicity and on new forms of excitatory transmitter neurotoxicity, with an aim toward evaluating how any of these neurotoxic processes might relate to the pathophysiology of memory impairment or neuronal degeneration in AD. The first specific aim pertains to L-cysteine, a unique but classical excitotoxin that destroys neurons by excessive activation of either of two EAA ionotropic receptor subtypes. The other two specific aims pertain to new mechanisms by which excitatory transmitter receptors can give rise to neuronal death. The second specific aim addresses a form of neurotoxicity that is triggered not by hyperstimulation but by suppression of a Glu ionotropic receptor which, according to recent evidence, results in excessive activation of cholinergic muscarinic receptors as the proximate cause of cerebrocortical neurodegenerative changes. In essence, this represents a new type of excitotoxicity which can properly be called """"""""cholinergic excitotoxicity"""""""". The third specific aim pertains to recent findings that hyperstimulation of a newly described EAA metabotropic receptor is associated with a distinctive neurotoxic reaction in specific neurons of the lateral septal nucleus. Each of these three specific aims pertains to neurodegenerative mechanisms that were originally discovered by the Program Director of this research program and leader of this Project. A wide range of neurochemical, neuropharmacological, neurohistological and molecular biological or immunobiological methods will be employed in the proposed research.
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