Lowering of extracellular pH suppresses low-Mg(2+)-induces seizures in combined entorhinal cortex-hippocampal slices.
Lowering [Mg2+]o induces epileptiform bursting in hippocampus and entorhinal cortex (EC), presumably by activation of N-methyl-D-aspartate (NMDA) receptors. Since increasing [H+]o has been shown to reduce NMDA receptor activation, we hypothesized that this could contribute to anticonvulsant actions of acidic pH. To test this, we studied the effects of raising extracellular PCO2 (20.6%, pH = 6.7) or lowering extracellular pH (6.7 or 6.2) on low-Mg(2+)-induced epileptiform discharges. Lowering the pH to 6.7 by either means increased the interval between seizure-like events (SLEs), decreased the maximal amplitude of SLEs, and if the site of seizure generation was at a distance from the recording site, acidification slowed the rate of seizure propagation. In contrast, the duration of SLEs was unaffected by acidic pH or high PCO2. Raising PCO2 or lowering pH to 6.7 also blocked early (8-10 min) but not late (> 20 min) phases of status-like discharges. All effects of the extracellular pH changes were fully reversible. Further lowering of extracellular pH to 6.2 completely and reversibly blocked both SLEs and status-like discharges. Our data show that the effects of high PCO2 and low pH on seizures in the EC in vitro may be dose-dependent and consistent with induction by proton blockade of NMDA receptors. Thus, blockade of NMDA currents by protons may be an important component of the anticonvulsant action of extracellular acidosis. The results also suggest that acidosis may be a desirable property for new antiepileptic treatments.
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461.
L
L
Velísek
J P
JP
Dreier
P K
PK
Stanton
U
U
Heinemann
S L
SL
Moshé
D000138:Acidosis / Q000503:physiopathology; D000818:Animals; D003470:Culture Media; D018728:Entorhinal Cortex / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008275:Magnesium Deficiency / Q000150:complications*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D013226:Status Epilepticus / Q000209:etiology / Q000503:physiopathology
D003470:Culture Media