Activation of NMDA receptors blocks GABAergic inhibition in an in vitro model of epilepsy.
The application of tetanic electrical stimuli to the stratum radiatum fibre pathway in the hippocampus in vitro produces an NMDA (N-methyl-D-aspartate) receptor-dependent enhancement of synaptic efficacy. Repeated application of such stimuli produces a progressive enhancement of synaptic efficacy leading to the genesis of spontaneous and stimulation-evoked epileptiform discharges. We have used this in vitro approach to explore the cellular mechanisms which underlie the kindling model of epilepsy. Kindling of the stratum radiatum fibre pathway in vitro induced a progressive, long-lasting reduction of both spontaneous and stimulation-evoked GABAergic (gamma-aminobutyric acid-mediated) inhibitory postsynaptic potentials (i.p.s.ps). The reduction of i.p.s.ps by kindling was associated with a profound decrease in the sensitivity of CA1 pyramidal neurons to ionophoretically applied GABA and an increase in sensitivity to NMDA. The reduction of i.p.s.ps and GABA sensitivity was prevented by kindling in the presence of the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (D-APV). These results demonstrate that kindling-like stimulus patterns produce a reduction of GABAergic inhibition in the hippocampus resulting from a stimulus-induced postsynaptic activation of NMDA receptors. The modulation of GABAergic inhibition by NMDA receptors may cause the synaptic plasticity which underlies the kindling model of epilepsy.
D015763:2-Amino-5-phosphonovalerate; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives; D004558:Electric Stimulation; D004827:Epilepsy / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects; D006168:Guinea Pigs; D006624:Hippocampus / Q000502:physiology* / Q000503:physiopathology; D066298:In Vitro Techniques; D011188:Potassium / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D005680:gamma-Aminobutyric Acid; D015763:2-Amino-5-phosphonovalerate; D014633:Valine; D011188:Potassium