Epileptiform activity in vitro can produce long-term synaptic failure and persistent neuronal depolarization.
A large, extracellular negative DC shift, termed epileptic depolarization, could be elicited during zero magnesium-induced epileptic activity in the rat hippocampal slice. In 10 mM glucose medium, epileptic depolarization was elicited by high-frequency synaptic stimulation. During epileptic depolarization synaptic responses were abolished, but recovered in 10.4 +/- 2.1 min. In low glucose (2 mM) medium, epileptic depolarization either occurred spontaneously or could be elicited by high frequency synaptic stimulation, and no recovery of synaptic responses was observed for at least 30 min. This long-term synaptic failure was blocked by the competitive NMDA antagonists, 3-[+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP, 100 microM) and D-2-amino-7-phosphonoheptanoate (D-AP7, 100 microM) when added at the peak of epileptic depolarization, but not 5 min afterwards. Intracellular analysis showed that this extracellular DC shift was correlated with a membrane depolarization which approached 0 mV. With 10 mM glucose medium, the membrane potential returned to resting level in 6.3 +/- 1.9 min. In 2 mM glucose medium, neurons remained depolarized and no recovery was observed. This persistent depolarization could account for the loss of synaptic function recorded extracellularly. Application of 100 microM CPP blocked persistent depolarization and allowed for the recovery of the membrane potential. Epileptic depolarization was also observed during picrotoxin-induced epileptic activity. Both anoxic depolarization during experimental ischemia and epileptic depolarization can trigger long-term synaptic failure and persistent depolarization. Epileptic depolarization and anoxic depolarization may be triggers which can lead to neuronal failure in diseases associated with neuronal degeneration.
Watson
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Central Nervous System Diseases Research, G.D. Searle & Company, Monsanto Company, Chesterfield, MO 63198.
Rader
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Lanthorn
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D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000200:Action Potentials; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D000596:Amino Acids; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D015763:2-Amino-5-phosphonovalerate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C031231:2-amino-7-phosphonoheptanoic acid