The experiments described in this grant application are designed to provide information about the participation of excitatory amino acids, especially glutamate, in neuronal death, development, and communication. They will utilize dispersed cultures of rat hippocampus and explant cultures to explore three aspects of the neurobiology of glutamate. These experiments should enhance our knowledge of events likely to take place during cerebral anoxin and ischemia, which are extremely important clinical problems. Major questions to be considered include: 1. What is the mechanism of glutamate neurotoxicity and how does it relate to anoxic neuronal injury? a. Is elevated intracellular calcium directly related to cell death? b. Is decreased intracellular pH directly related to cell death? c. Are perturbations of second messengers/modulators/intracellular enzymes causally linked to neuronal death? d. Are there circumstances when glutamate alters neurons without killing them? e. What is the sequence of morphological changes which neurons undergo prior to glutamate-induced death? 2. Does ongoing release of glutamate alter the structure or function of developing neurons? a. Will chronic blockage of glutamate receptors modify the dendritic structure of hippocampal neurons? b. Is the level of intracellular calcium in cultured neurons partially regulated by ongoing glutamate release and synaptic activity? 3. What factors control the release of synaptic glutamate in vitro? a. What is the peak concentration of glutamate released-into the synaptic cleft? b. Is calcium always required for glutamate release?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS019988-08
Application #
3400139
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1983-09-10
Project End
1996-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
8
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Rothman, S M (1999) Mutations of the mitochondrial genome: clinical overview and possible pathophysiology of cell damage. Biochem Soc Symp 66:111-22
Werth, J L; Park, T S; Silbergeld, D L et al. (1998) Excitotoxic swelling occurs in oxygen and glucose deprived human cortical slices. Brain Res 782:248-54
Handran, S D; Werth, J L; DeVivo, D C et al. (1997) Mitochondrial morphology and intracellular calcium homeostasis in cytochrome oxidase-deficient human fibroblasts. Neurobiol Dis 3:287-98
Yamada, K A; Turetsky, D M (1996) Allosteric interactions between cyclothiazide and AMPA/kainate receptor antagonists. Br J Pharmacol 117:1663-72
Holland, K D; Mathews, G C; Bolos-Sy, A M et al. (1995) Dual modulation of the gamma-aminobutyric acid type A receptor/ionophore by alkyl-substituted gamma-butyrolactones. Mol Pharmacol 47:1217-23
Dugan, L L; Sensi, S L; Canzoniero, L M et al. (1995) Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J Neurosci 15:6377-88
White, L E; Hodges, H D; Carnes, K M et al. (1994) Colocalization of excitatory and inhibitory neurotransmitter markers in striatal projection neurons in the rat. J Comp Neurol 339:328-40
Dubinsky, J M (1993) Effects of calcium chelators on intracellular calcium and excitotoxicity. Neurosci Lett 150:129-32
Rothman, S M; Yamada, K A; Lancaster, N (1993) Nordihydroguaiaretic acid attenuates NMDA neurotoxicity--action beyond the receptor. Neuropharmacology 32:1279-88
Yamada, K A; Tang, C M (1993) Benzothiadiazides inhibit rapid glutamate receptor desensitization and enhance glutamatergic synaptic currents. J Neurosci 13:3904-15

Showing the most recent 10 out of 30 publications