The long term goal of this project is to determine the physiological and biochemical mechanisms by which endogenous excitatory amino acids, such as glutamic acid, become toxic to neurons of the brain under pathological conditions. Quisqualic acid is a neurotoxic excitatory amino acid isolated from the seeds of certain tropical plants. It sensitizes brain slice preparations to depolarization by phophonate analogs of excitatory amino acids. Both the sensitization by quisqualate and its toxicity exhibit similar pharmacological profiles and are proposed to occur by a mechanism that involves uptake and the subsequent release of quisqualate or another excitatory amino acid agonist, A detailed model is proposed for quisqualate sensitization and quisqualate toxicity. This model involves quisqualate uptake into a specific subset of hippocampal interneurons. Quisqualate release then occurs at a slow background rate which can be enhanced by various effectors. The release of quisqualate facilitates depolarization of postsynaptic neurons and eventually elicits signs of excitotoxicity.
The Specific Aims for this project are: a) To obtain experimental evidence that supports an """"""""Uptake and Release"""""""" hypothesis for quisqualate sensitization and toxicity. b) To replicate the mechanisms of quisqualate uptake/release in synaptosomal preparations showing parallel pharmacological properties to quisqualate sensitization, thereby make it possible to study the putative uptake/release systems at the biochemical level. c) To further characterize the hippocampal interneurons that exhibit quisqualate uptake mechanisms, and to determine whether these interneurons represent a novel subset of neurons or are identical to a subset previously implicated in cytotoxic mechanisms. Investigations of these mechanisms at the cell biological and biochemical level will clarify their functioning and roles in the normal brain. They will also contribute to understanding of the neurotoxicity of glutamate and other excitatory amino acids. These toxic responses are also triggered by ischemia and may be the basis for the neuronal damage that accompanies stroke.
| Chase, L A; Peterson, N L; Koerner, J F (2007) The lathyrus toxin, beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (ODAP), and homocysteic acid sensitize CA1 pyramidal neurons to cystine and L-2-amino-6-phosphonohexanoic acid. Toxicol Appl Pharmacol 219:1-9 |
| Chase, L A; Roon, R J; Wellman, L et al. (2001) L-Quisqualic acid transport into hippocampal neurons by a cystine-sensitive carrier is required for the induction of quisqualate sensitization. Neuroscience 106:287-301 |
