It is estimated that up to 1 % of the population in the United States has recurrent seizures, among which involvement of the temporal lobe and hippocampus is common. The goal of this research is to study the postictal changes in the physiological and behavioral functions of the hippocampus following experimentally induced seizures in animals, using the kindling model of temporal lobe epilepsy. In the previous grant period, we have found a long-lasting working memory deficit after hippocampal kindling in rats, as well as a decrease in paired-pulse inhibition of the extracellular response in CA1. The first major area of this proposal is to study the changes in electrophysiology after repeated afterdischarges (ADs) delivered to CA1 (CA1 kindling). In rats with chronically implanted electrodes, the change of the population (extracellular) excitatory postsynaptic potentials and population spike in CA1 (an extracellularly recorded signal corresponding to synchronous firing of a population of CA1 neurons) evoked by commissural or association fibers, at the basal or apical dendrites of CA1 pyramidal cells, will be assessed following repeated ADs. Paired-pulse responses, a sensitive measure of evoked inhibition, will also be recorded. In parallel experiments done at various times after in vivo kindling, the in vitro electrophysiology in CA1 cells, following single- or paired- pulse stimulation of the afferent fibers, is studied by intracellular recordings under current- or voltage-clamp condition, using conventional or patch electrodes . The in vitro experiments are designed to identify whether GABA-A and GABA-B-mediated inhibition, stimulus-evoked extracellular potassium concentration, excitation through N-methyl-D-aspartate (NMDA) and non-NMDA receptors, and intrinsic properties of single neurons are modified after kindling. A second major area of this proposal is to characterize the behavioral dysfunctions following kindling. Experiments are designed on the radial 8-arm maze and in the Morris swim pool to investigate whether the behavioral dysfunction applies to reference as well as working memory, to non-spatial as well as spatial tasks, and to task acquisition in addition to retention. The hypothesis whether paired-pulse disinhibition in CA1 is a cause of the task retention deficit will be evaluated by systematic variation of the kindling procedure and by induction of CA1 disinhibition by direct bicuculline injections. The set of experiments should reveal the kind and magnitude of the physiological and behavioral changes induced by (kindled) seizures, an area difficult to study in epileptic patients. Understanding of these postictal changes may offer a new treatment of some neural and behavioral dysfunctions in patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025383-06
Application #
2265551
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-02-01
Project End
1995-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Western Ontario
Department
Type
DUNS #
208469452
City
London
State
ON
Country
Canada
Zip Code
N6 3-K7
Wu, K; Canning, K J; Leung, L S (1998) Functional interconnections between CA3 and the dentate gyrus revealed by current source density analysis. Hippocampus 8:217-30
Wu, K; Leung, L S (1998) Monosynaptic activation of CA3 by the medial perforant path. Brain Res 797:35-41
Leung, L S (1998) Generation of theta and gamma rhythms in the hippocampus. Neurosci Biobehav Rev 22:275-90
Wu, C; Leung, L S (1997) Partial hippocampal kindling decreases efficacy of presynaptic GABAB autoreceptors in CA1. J Neurosci 17:9261-9
Leung, L S; Brzozowski, D; Shen, B (1996) Partial hippocampal kindling affects retention but not acquisition and place but not cue tasks on the radial arm maze. Behav Neurosci 110:1017-24
Ma, J; Brudzynski, S M; Leung, L W (1996) Involvement of the nucleus accumbens-ventral pallidal pathway in postictal behavior induced by a hippocampal afterdischarge in rats. Brain Res 739:26-35
Leung, L S; Roth, L; Canning, K J (1995) Entorhinal inputs to hippocampal CA1 and dentate gyrus in the rat: a current-source-density study. J Neurophysiol 73:2392-403
Leung, L S; Zhao, D (1995) Glial potentials evoked by single afferent pulses in hippocampal CA1 area in vitro. Brain Res 697:262-5
Leung, L S; Shen, B (1995) Long-term potentiation at the apical and basal dendritic synapses of CA1 after local stimulation in behaving rats. J Neurophysiol 73:1938-46
Leung, L W (1995) Simulation of perforant path evoked field and intracellular potentials in hippocampal CA1 area. Hippocampus 5:129-36

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