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-met hyl-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 h ippocampal slices from kindled and normal rats. In agreement with previous studies, granule cells from kindled rats examined within 1 wk after the las t of 3 or 30-35 generalized tonic-clonic (class V) seizures demonstrated an increase in the NMDA receptor-dependent component of the perforant path-ev oked synaptic current. Within 1 wk of the last kindled seizure, NMDA-depend ent charge transfer underlying the perforant path-evoked current was increa sed by 63-111% at a holding potential of -30 mV. In contrast, the NMDA-depe ndent component of the perforant-evoked current in granule cells examined a t 2.5-3 mo after the last of 3 or 90-120 class V seizures did not differ fr om age-matched controls. Because the seizure-induced increases in NMDA-depe ndent synaptic currents declined toward control Values during a time course of 2.5-3 mo, increases in NMDA-dependent synaptic transmission cannot acco unt for the permanent susceptibility to evoked and spontaneous seizures ind uced by kindling. The increase in NMDA receptor-dependent transmission was associated with the induction of kindling but was not responsible for the m aintenance of the kindled state. The time course of alterations in NMDA-dep endent synaptic current and the dependence of the progression of kindling a nd kindling-induced mossy fiber sprouting on repeated NMDA receptor activat ion are consistent with the possibility that the NMDA receptor is part of a transmembrane signaling pathway that induces long-term cellular alteration s and circuit remodeling in response to repeated seizures, but is not requi red for permanent seizure susceptibility in circuitry altered by kindling.