The principal excitatory neurotransmitters in the CNS -- glutamate (Glu) and acetylcholine -- have important physiological functions, including the mediation of cognition and memory, but also possess significant neurotoxic potential. In this project, the applicants will focus on three different forms of excitatory transmitter neurotoxicity, with an aim toward evaluating how these neurotoxic processes might relate to the pathophysiology of memory impairment or neurodegenerative processes that occur in humans. The first specific aim addresses a new form of neurotoxicity that is triggered 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 type of neurotoxic reaction can properly be called """"""""cholinergic excitotoxicity"""""""". The second specific aim pertains to recent findings that neuronal degeneration occurs in association with drug treatments that cause hyperstimulation of the second messenger functions of a newly described EAA metabotropic receptor. The third specific aim pertains to the neurotoxicity of domoate, a Glu analog recently implicated in a food poisoning incident in which adult humans, especially elderly humans, sustained brain damage and memory loss. The first two specific aims pertain to neurotoxic syndromes that are also being addressed by different methods in Dr. Olney's proposal (Project #1). The research proposed in the present project emphasizes the application of specialized histological methods, including electron microscopic immunocytochemistry, in situ hybridization histochemistry and receptor autoradiography, whereas in Dr. Olney's proposal the emphasis is predominantly on neuropharmacological and neurotoxicological approaches. This is the only project in this program projects proposal that addresses domoate neurotoxicity; however, this work will be performed in coordination with other on going studies by Dr. Wozniak pertaining to domoate-induced memory impairment.
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