Synaptic regulation of the slow Ca2+-activated K+ current in hippocampal CA1 pyramidal neurons: Implication in epileptogenesis

The slow Ca2+-activated K+ current (sI(AHP)) plays a critical role in regul ating neuronal excitability, but its modulation during abnormal bursting ac tivity, as in epilepsy, is unknown. Because synaptic transmission is enhanc ed during epilepsy, we investigated the synaptically mediated regulation of the sI(AHP) and its control of neuronal excitability during epileptiform a ctivity induced by 4-aminopyridine (4AP) or 4AP+Mg2+-free treatment in rat hippocampal slices. We used electrophysiological and photometric Ca2+ techn iques to analyze the sI(AHP) modifications that parallel epileptiform activ ity. Epileptiform activity was characterized by slow, repetitive, spontaneo us depolarizations and action potential bursts and was associated with incr eased frequency and amplitude of spontaneous excitatory postsynaptic curren ts and a reduced sI(AHP). The metabotropic glutamate receptor (mGluR) antag onist (S)-alpha -methyl-4-carboxyphenylglycine did not modify synaptic acti vity enhancement but did prevent sI(AHP) inhibition and epileptiform discha rges. The mGluR-dependent regulation of the sI(AHP) was not caused by modul ated intracellular Ca2+ signaling. Histamine, isoproterenol, and (+/-)-1-am inocyclopentane-trans-1,3-dicarboxylic acid reduced the sI(AHP) but did not increase synaptic activity and failed to evoke epileptiform activity. We c onclude that 4AP or 4AP+Mg-free-induced enhancement of synaptic activity re duced the sI(AHP) via activation of postsynaptic group I/II mGluRs. The inc reased excitability caused by the lack of negative feedback provided by the sI(AHP) contributes to epileptiform activity, which requires the cooperati ve action of increased synaptic activity.