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 regulating neuronal excitability, but its modulation during abnormal bursting activity, as in epilepsy, is unknown. Because synaptic transmission is enhanced during epilepsy, we investigated the synaptically mediated regulation of the sI_AHP and its control of neuronal excitability during epileptiform activity induced by 4-aminopyridine (4AP) or 4AP+Mg²⁺-free treatment in rat hippocampal slices. We used electrophysiological and photometric Ca²⁺ techniques to analyze the sI_AHP modifications that parallel epileptiform activity. Epileptiform activity was characterized by slow, repetitive, spontaneous depolarizations and action potential bursts and was associated with increased frequency and amplitude of spontaneous excitatory postsynaptic currents and a reduced sI_AHP. The metabotropic glutamate receptor (mGluR) antagonist (S)-α-methyl-4-carboxyphenylglycine did not modify synaptic activity enhancement but did prevent sI_AHP inhibition and epileptiform discharges. The mGluRdependent regulation of the sI_AHP was not caused by modulated intracellular Ca²⁺ signaling. Histamine, isoproterenol, and(±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid reduced the sI_APH but did not increase synaptic activity and failed to evoke epileptiform activity. We conclude that 4AP or 4AP+Mg-free-induced enhancement of synaptic activity reduced the sI_AHP via activation of postsynaptic group I/II mGluRs. The increased excitability caused by the lack of negative feedback provided by the sI_AHP contributes to epileptiform activity, which requires the cooperative action of increased synaptic activity.