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Enhanced GABAergic inhibition preserves hippocampal structure and function in a model of epilepsy.

Abstract
Extensive electrical stimulation of the perforant pathway input to the hippocampus results in a characteristic pattern of neuronal death, which is accompanied by an impairment of cognitive functions similar to that seen in human temporal lobe epilepsy. The excitotoxic hypothesis of epileptic cell death [Olney, J. W. (1978) in Kainic Acid as a Tool in Neurobiology, eds. McGeer, E., Olney, J. W. & McGeer, P. (Raven, New York), pp. 95-121; Olney, J. W. (1983) in Excitotoxins, eds. Fuxe, K., Roberts, P. J. & Schwartch, R. (Wenner-Gren International Symposium Series, Macmillan, London), Vol. 39, pp. 82-96; and Rothman, S. M. & Olney, J. W. (1986) Ann. Neurol. 19, 105-111] predicts an imbalance between excitation and inhibition, which occurs probably as a result of hyperactivity in afferent pathways or impaired inhibition. In the present study, we investigated whether the enhancement of gamma-aminobutyric acid (GABA)-mediated (GABAergic) inhibition of neurotransmission by blocking the GABA-metabolizing enzyme, GABA transaminase, could influence the histopathological and/or the behavioral outcome in this epilepsy model. We demonstrate that the loss of pyramidal cells and hilar somatostatin-containing neurons can be abolished by enhancing the level of synaptically released GABA, and that the preservation of hippocampal structure is accompanied by a significant sparing of spatial memory as compared with placebo-treated controls. These results suggest that enhanced GABAergic inhibition can effectively block the pathophysiological processes that lead to excitotoxic cell death and, as a result, protect the brain from seizure-induced cognitive impairment.
AuthorsA M Ylinen, R Miettinen, A Pitkänen, A I Gulyas, T F Freund, P J Riekkinen
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 88 Issue 17 Pg. 7650-3 (Sep 01 1991) ISSN: 0027-8424 [Print] United States
PMID1652757 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • gamma-Aminobutyric Acid
  • 4-Aminobutyrate Transaminase
Topics
  • 4-Aminobutyrate Transaminase (metabolism)
  • Animals
  • Electric Stimulation
  • Electroencephalography
  • Epilepsy (pathology, physiopathology)
  • Hippocampus (pathology, physiology, physiopathology)
  • Male
  • Models, Neurological
  • Neurons (cytology, pathology, physiology)
  • Rats
  • Rats, Inbred Strains
  • Synapses (physiology)
  • Synaptic Transmission
  • gamma-Aminobutyric Acid (physiology)

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