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Activation of a Calcium-Activated Cation Current During Epileptiform Discharges and Its Possible Role in Sustaining Seizure-Like Events in Neocortical Slices

Department of Neurology, Rambam Medical Center and Technion Medical School, Haifa 31096, Israel

Submitted 18 October 2003; accepted in final form 18 March 2004

Epileptic seizures are composed of recurrent bursts of intense firing separated by periods of electrical quiescence. The mechanisms responsible for sustaining seizures and generating recurrent bursts are yet unclear. Using whole cell voltage recordings combined with intracellular calcium fluorescence imaging from bicuculline (BCC)-treated neocortical brain slices, I showed isolated paroxysmal depolarization shift (PDS) discharges were followed by a sustained afterdepolarization waveform (SADW) with an average peak amplitude of 3.3 ± 0.9 mV and average half-width of 6.2 ± 0.6 s. The SADW was mediated by the calcium-activated nonspecific cation current (I_can) as it had a reversal potential of –33.1 ± 6.8 mV, was unaffected by changing the intracellular chloride concentrations, was markedly diminished by buffering [Ca²⁺]_i with intracellular bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA), and was reversibly abolished by the I_can blocker flufenamic acid (FFA). The Ca²⁺ influx responsible for activation of I_can was mediated by both N-methyl-D-aspartate-receptor channels, voltage-gated calcium channels and, to a lesser extent, internal calcium stores. In addition to isolated PDS discharges, BCC-treated brain slices also produced seizure-like events, which were accompanied by a prolonged depolarizing waveform underlying individual ictal bursts. The similarities between the initial part of this waveform and the SADW and the fact it was markedly reduced by buffering [Ca²⁺]_i with BAPTA strongly suggested it was mediated, at least in part, by I_can. Addition of FFA reversibly eliminated recurrent bursting, and transformed seizure-like events into isolated PDS responses. These results indicated I_can was activated during epileptiform discharges and probably participated in sustaining seizure-like events.

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