NMDA-dependent currents in granule cells of the dentate gyrus contribute to induction but not permanence of kindling.
Single-electrode voltage-clamp techniques and bath application of the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV) were used to study the time course of seizure-induced alterations in NMDA-dependent synaptic currents in granule cells of the dentate gyrus in hippocampal slices from kindled and normal rats. In agreement with previous studies, granule cells from kindled rats examined within 1 wk after the last of 3 or 30-35 generalized tonic-clonic (class V) seizures demonstrated an increase in the NMDA receptor-dependent component of the perforant path-evoked synaptic current. Within 1 wk of the last kindled seizure, NMDA-dependent charge transfer underlying the perforant path-evoked current was increased by 63-111% at a holding potential of -30 mV. In contrast, the NMDA-dependent component of the perforant-evoked current in granule cells examined at 2.5-3 mo after the last of 3 or 90-120 class V seizures did not differ from age-matched controls. Because the seizure-induced increases in NMDA-dependent synaptic currents declined toward control values during a time course of 2.5-3 mo, increases in NMDA-dependent synaptic transmission cannot account for the permanent susceptibility to evoked and spontaneous seizures induced by kindling. The increase in NMDA receptor-dependent transmission was associated with the induction of kindling but was not responsible for the maintenance of the kindled state. The time course of alterations in NMDA-dependent synaptic current and the dependence of the progression of kindling and kindling-induced mossy fiber sprouting on repeated NMDA receptor activation are consistent with the possibility that the NMDA receptor is part of a transmembrane signaling pathway that induces long-term cellular alterations and circuit remodeling in response to repeated seizures, but is not required for permanent seizure susceptibility in circuitry altered by kindling.
Department of Neurology, University of Wisconsin, William S. Middleton Veterans Administration Hospital, Madison 53792, USA.
Sayin
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Rutecki
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Sutula
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D018891:Dentate Gyrus / Q000502:physiology*; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D007696:Kindling, Neurologic / Q000502:physiology*; D008297:Male; D016202:N-Methylaspartate / Q000502:physiology*; D018408:Patch-Clamp Techniques; D019580:Perforant Pathway / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000503:physiopathology; D013569:Synapses / Q000502:physiology; D013995:Time
D018691:Excitatory Amino Acid Antagonists; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate