Abstracts

RATIONALE: Epileptic seizures are characterized by increased hyper-synchronous electrical activity in cortical neurons. The ionic mechanisms responsible for maintaining electrical activity during seizures remain elusive.
METHODS: Concomitant whole-cell recordings from the soma and apical dendrites of layer-5 pyramidal neurons combined calcium fluorescence imaging in neocortical brain slices bathed in an extracellular slution containing either Bicuculline or zero magnesium.
RESULTS: In Bicuculline treated brain slices electrographic seizures were associated with an underlying sustained depolarizing waveform (SDW). The SDW had an average amplitude of 12.7[plusminus]1.1 mV, an average half-width of 13.3[plusminus]1.4 seconds, and average reversal potential of [ndash]9.1[plusminus]2.8 mV, as recorded at the soma. The SDW was calcium dependent, as it was markedly attenuated by loading neurons with the intracellular calcium buffer BAPTA via the recording pipette. Taken together the above described findings indicated the SDW was mediated by a calcium-activated cationic current. Concomitant recordings from the soma and apical dendrite of the same neuron revealed that the amplitude of the SDW was larger at the soma. Addition of Flufenamic acid, a selective blocker of the calcium-activated cationic current (Ican), reversibly abolished the SDW. Concomitantly it reversibly eliminated spontaneous electrographic seizures and transformed evoked electrographic seizures into inter-ictal like discharges. Similar results were obtained in a second model of acute experimental epilepsy, neocortical slices bathed in a magnesium free solution.
CONCLUSIONS: The formation and maintenance of electrographic seizures critically depend on the calcium-activated cationic current, and as such the calcium-activated cationic current may serve as a novel target for anti-epileptic therapy.
[Supported by: The Yael Foundation]