Synaptic Regulation of the Slow Ca-Activated K Current in Hippocampal CA1 Pyramidal Neurons: Implication in Epileptogenesis

Martı́n, Eduardo D., Alfonso Araque, and Washington Buño. Synaptic regulation of the slow Ca-activated K current in hippocampal CA1 pyramidal neurons: implication in epileptogenesis. J Neurophysiol 86: 2878–2886, 2001. The slow Ca-activated K current (sIAHP) 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 sIAHP and its control of neuronal excitability during epileptiform activity induced by 4-aminopyridine (4AP) or 4AP1Mg-free treatment in rat hippocampal slices. We used electrophysiological and photometric Ca techniques to analyze the sIAHP 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 sIAHP. The metabotropic glutamate receptor (mGluR) antagonist (S)-a-methyl-4-carboxyphenylglycine did not modify synaptic activity enhancement but did prevent sIAHP inhibition and epileptiform discharges. The mGluRdependent regulation of the sIAHP was not caused by modulated intracellular Ca signaling. Histamine, isoproterenol, and (6)-1aminocyclopentane-trans-1,3-dicarboxylic acid reduced the sIAHP but did not increase synaptic activity and failed to evoke epileptiform activity. We conclude that 4AP or 4AP1Mg-free–induced enhancement of synaptic activity reduced the sIAHP via activation of postsynaptic group I/II mGluRs. The increased excitability caused by the lack of negative feedback provided by the sIAHP contributes to epileptiform activity, which requires the cooperative action of increased synaptic activity.