Potentiation of inhibition with perforant path kindling: an NMDA-receptor dependent process.
Kindling produces a long-lasting enhancement of excitatory and inhibitory neurotransmission. Both long-term potentiation and kindling-induced potentiation of hippocampal excitatory neurotransmission are suppressed by N-methyl-D-aspartate (NMDA) receptor antagonists. These antagonists also greatly retard the development of electrical kindling. We have previously reported prolonged afterdischarges (AD) in animals stimulated in the perforant path and treated with the NMDA antagonist, dizocilpine maleate (MK-801), despite a retardation in the development of kindling. In the present study the potentiation of excitation and inhibition was assessed during perforant path kindling when NMDA channels were blocked with MK-801. Paired pulse inhibition at 8 interpulse intervals (IPI 20-1000 ms) was monitored before and during kindling development. MK-801 (1 mg/kg, i.p.) delivered 30 min prior to perforant path stimulation increased AD thresholds and delayed kindling development. Potentiation of the excitatory postsynaptic potential (EPSP) and of paired pulse inhibition measured 20-24 h after each drug administration/stimulation were suppressed in MK-801-treated animals. Paradoxically, AD durations were prolonged by MK-801. Longer AD durations could be accounted for by a higher incidence of secondary AD bouts in MK-801 relative to control animals. Development of potentiation of the early phase of paired pulse inhibition (IPI 20-30 ms) was delayed and the potentiation of the late phase of inhibition (IPIs of 200-1000 ms) was completely blocked by MK-801. Thus, some of the enhancement of inhibition seen with kindling is dependent upon NMDA neurotransmission. Suppression of this potentiated inhibition may account for prolonged focal ADs in the perforant path and dentate gyrus.
Gilbert
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ME
Mantech Environmental Technology Incorporated, Research Triangle Park, NC 27709.
D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000502:physiology; D006624:Hippocampus / Q000502:physiology; D007696:Kindling, Neurologic / Q000502:physiology*; D008297:Male; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013569:Synapses / Q000502:physiology
D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate