Glutamate (GLU), or a closely related compound, is believed to be the primary excitatory neurotransmitter in mammalian brain. A better understanding of the glutamatergic system could influence treatment for epilepsy, brain ischemia and several other important neurological diseases. This project proposes exploration of new concepts pertaining to the physiology of glutamate (GLU) and related amino acids in vertebrate brain, using intracellular recordings in rat hippocampal slice. Section 1 will investigate endogenous dipeptides containing glutamate (GLU), recently shown by the P.I. to be physiologically active in regions of presumed glutamatergic synapses. The candidicy of these dipeptides as CNS neurotransmitters or neuromodulators will be studied by ascertaining ionic dependencies, pharmacology and action on hippocampal neurons. Section 2 will examine how glutamatergic transmission is regulated in the presence of excessive GLU (1-2 mM for 1-5 minutes), reflecting a type of """"""""desensitization"""""""". This will be among the first detailed studies of GLU desensitization in mammalian brain using intracellular techniques. First, we will establish that GLU desensitization occurs, and specify the experimental parameters needed to produce it. Second, we will document that evoked EPSPs decline concurrently with desensitization to GLU. This EPSP decline will be shown to result from a block in synaptic transmission at specific excitatory, but not inhibitory, hippocampal pathways. Miniature EPSP analysis will indicate if the block of the EPSP by exposure to GLU is mediated pre- or post-synaptically. The contributions of the receptor subtype agonists, N-methyl-D-aspartate, quisqualate and kainate, to GLU desensitization will be studied. Agents that enhance GLU desensitization in invertebrate systems (such as lectins) will be studied in hippocampus.
| Aryanpur, J; Cole, A E; Eccles, C U et al. (1990) Biphasic action of dextrorphan on penicillin induced bursting in rat hippocampal slice. Brain Res 519:65-72 |
| Krauss, G L; Kaplan, P; Fisher, R S (1989) Parenteral magnesium sulfate fails to control electroshock and pentylenetetrazol seizures in mice. Epilepsy Res 4:201-6 |
| Fisher, R S (1989) Animal models of the epilepsies. Brain Res Brain Res Rev 14:245-78 |
| Cole, A E; ffench-Mullen, J M; Fisher, R S (1989) Fade of the response to prolonged glutamate application in the rat hippocampal slice. Synapse 4:11-8 |
| Fisher, R S; Cysyk, B (1988) A fatal overdose of carbamazepine: case report and review of literature. J Toxicol Clin Toxicol 26:477-86 |
| Fisher, R S; Kaplan, P W; Krumholz, A et al. (1988) Failure of high-dose intravenous magnesium sulfate to control myoclonic status epilepticus. Clin Neuropharmacol 11:537-44 |
