Seizures that begin in limbic structures (partial complex seizures) remain difficult to adequately control in humans. An animal model that closely replicates these seizures is kindling, The mechanisms that initiate and terminate after-discharges in the kindling model are unknown. Recently, a distinct electrophysiological event linked to kindled seizures has been identified in the anesthetized rat, This event is called maximal dentate activation and consists of the sudden appearance of bursts of large amplitude population spikes of the granule cells in the dentate gyrus. The elicitation of maximal dentate activation has been shown to be a critical step in the production of a hippocampal afterdischarge and in the lengthening of afterdischarges that occur during kindling. The long-term objectives of this project are to understand the synaptic and cellular mechanisms underlying the initiation and termination of maximal dentate activation and, therefore, afterdischarges.
Specific aims i nclude: 1) determination of the anatomical regions within the limbic circuit that are necessary for the generation and maintenance of maximal dentate activation, 2) determination of the neurotransmitter or neuromodulator systems that influence the initiation or duration of maximal dentate activation, 3) determination of the cellular basis of maximal dentate activation. The experiments use a combination of in vivo and in vitro techniques to explore these areas. The in vivo experiments in urethane-anesthetized rats use multiple extracellular recordings and lesions to examine the parts of the limbic system that are critical in the control of maximal dentate activation. In all instances recording is done in the dentate gyrus for comparison purposes. Pharmaceutical agents will be used to begin to address the issue of neurotransmitter/neuromodulator influence on the initiation and duration of maximal dentate activation. Drugs that potentiate and inhibit the excitatory and inhibitory systems, as well as agents that alter cholinergic and adenosinergic inputs will be tested. Brain slices that include the hippocampus, subiculum, and entorhinal cortex will be used to examine the cellular basis of maximal dentate activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS028871-05
Application #
3478146
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1990-09-20
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
5
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Stringer, J L; Erden, F (1995) In the hippocampus in vivo, nitric oxide does not appear to function as an endogenous antiepileptic agent. Exp Brain Res 105:391-401
Stringer, J L; Higgins, M G (1994) Interaction of phenobarbital and phenytoin in an experimental model of seizures in rats. Epilepsia 35:216-20
Stringer, J L; Sowell, K L (1994) Kainic acid, bicuculline, pentylenetetrazol and pilocarpine elicit maximal dentate activation in the anesthetized rat. Epilepsy Res 18:11-21
Stringer, J L; Colbert, C M (1994) Analysis of field potentials evoked in Ca1 by angular bundle stimulation in the rat. Brain Res 641:289-94
Stringer, J L; Higgins, M G (1994) Pharmacological characterization of the afterdischarge that precedes the onset of maximal dentate activation in the rat. Neuropharmacology 33:625-33
Stringer, J L (1994) Pentylenetetrazol elicits epileptiform activity in the dentate gyrus of the urethane anesthetized rat by activation of the entorhinal cortex. Brain Res 636:221-6
Bonthius, D J; Stringer, J L; Lothman, E W et al. (1994) Spreading depression and reverberatory seizures induce the upregulation of mRNA for glial fibrillary acidic protein. Brain Res 645:215-24
Stringer, J L (1994) Valproic acid and ethosuximide slow the onset of maximal dentate activation in the rat hippocampus. Epilepsy Res 19:229-35
Stringer, J L (1993) Alterations in both excitation and inhibition occur before the onset of seizure activity in the hippocampus. Epilepsy Res 16:99-109
Stringer, J L (1993) Repeated seizures cause a generalized increase in excitability in the hippocampus. Neurosci Lett 150:223-6

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