Enhanced GABAergic inhibition preserves hippocampal structure and function in a model of epilepsy.
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.
Ylinen
A M
AM
Department of Neurology, University of Kuopio, Finland.
Miettinen
R
R
Pitkänen
A
A
Gulyas
A I
AI
Freund
T F
TF
Riekkinen
P J
PJ
D000612:4-Aminobutyrate Transaminase / Q000378:metabolism; D000818:Animals; D004558:Electric Stimulation; D004569:Electroencephalography; D004827:Epilepsy / Q000473:pathology / Q000503:physiopathology*; D006624:Hippocampus / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000473:pathology / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase