Mechanisms underlying the neuropathological consequences of epileptic activity in the rat hippocampus in vitro.
Blockage of gamma-aminobutyric acid (GABA)ergic synaptic transmission in mature hippocampal slice cultures for a period of 3 days with convulsants was shown previously to induce chronic epileptiform activity and to mimic many of the degenerative changes observed in the hippocampi of epileptic humans. The cellular mechanisms underlying the induction of this degeneration were examined in the present study by comparing the effects of GABA blockers with the effects produced by the K+ channel blocker tetraethylammonium (2 mM). Both types of convulsant caused a comparable decrease in the number of Nissl-stained pyramidal cells in areas CA1 and CA3. No significant cell loss was induced by tetraethylammonium when epileptiform discharge was reduced by simultaneous exposure of cultures to tetrodotoxin (0.5 microM) or to the anticonvulsants pentobarbital (50 microM) or tiagabine (50 microM). We conclude that this degeneration was mediated by convulsant-induced epileptiform discharge itself. The hypothesis that N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity underlies cell death in this model was tested by applying convulsants together with specific antagonists of glutamate receptors. Whereas coapplication of antagonists of both non-NMDA and NMDA receptors strongly reduced the degeneration induced by the convulsants, application of either class of antagonist alone did not. Application of exogenous NMDA produced potent cell death, and this degeneration was blocked by the NMDA receptor antagonist methyl-10,11-dihydro-5-H-dibenzocyclohepten-5,10-imine (MK-801). Convulsants also induced a loss of dendritic spines that could be partially prevented by NMDA or non-NMDA receptor antagonists. We conclude that NMDA receptor activation is not solely responsible for the neuronal pathology resulting as a consequence of epileptiform discharge.
Thompson
S M
SM
Brain Research Institute, University of Zurich, Switzerland. Thompson@hifo.unizh.ch
Fortunato
C
C
McKinney
R A
RA
Müller
M
M
Gähwiler
B H
BH
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D003292:Convulsants / Q000633:toxicity*; D003712:Dendrites / Q000187:drug effects; D004827:Epilepsy / Q000139:chemically induced / Q000473:pathology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000473:pathology*; D066298:In Vitro Techniques; D009410:Nerve Degeneration / Q000187:drug effects*; D051381:Rats
D000927:Anticonvulsants; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists