Epileptiform activity and EPSP-spike potentiation induced in rat hippocampal CA1 slices by repeated high-K(+): involvement of ionotropic glutamate receptors and Ca(2+)/calmodulin-dependent protein kinase II.

We have previously demonstrated that repeated brief increases in extracellular K(+) (K(+)(o)) induce a hyperexcitability in CA1 pyramidal cells that persists for a long time after the final application of K(+) [Neurosci. Lett. 223 (1997) 177; Epilepsy Research (2000) 75]. This epileptiform activity, which was associated with a lasting excitatory postsynaptic potential (EPSP)-spike potentiation, presented some of the characteristic features of traditional in vivo kindling. We have also found that Ca(2+) influx through L-type voltage-sensitive Ca(2+) channels is essential for the development of both in vitro kindling and EPSP-spike potentiation. The aims of this study were to investigate the involvement of ionotropic glutamate receptors, especially those of the NMDA subtype, and the requirement for Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in these phenomena. Field EPSPs with presynaptic fibre volleys from the stratum radiatum, and population spikes from the stratum pyramidale, were recorded in the CA1 area of rat hippocampal slices in response to electrical stimulation of the Schaffer collateral/commissural fibres. Repeated (three episodes) brief (30 s) increases in extracellular K(+) induced a sustained decrease in the threshold for development of evoked epileptiform discharges (i.e. an in vitro kindling-like state) and a lasting potentiation of the EPSP-spike transfer in CA1 pyramidal neurons (EPSP-spike potentiation). The selective antagonist of NMDA receptors, APV (50 microM), blocked the EPSP-spike potentiation, depressed the induction phase of the in vitro kindling-like state, and blocked the maintenance phase of this state. In contrast to APV, the blockade of AMPA/kainate receptors by CNQX (10 microM) had no effect. Like APV, KN62 (3 microM), a selective membrane permeable inhibitor of CaMKII, blocked the EPSP-spike potentiation and the maintenance phase of the in vitro kindling-like state. Our previous and present results therefore demonstrate that Ca(2+) influxes through L-type voltage-dependent-and NMDA receptor-dependent-Ca(2+) channels contribute differentially to the development of an in vitro kindling-like state, and both induce EPSP-spike potentiation in CA1 hippocampal pyramidal cells in response to repeated brief increases in K(+)(o). It is suggested that these effects of intracellular Ca(2+) on the maintenance phase of the in vitro kindling-like state and EPSP-spike potentiation are mediated by CaMKII-dependent mechanisms.