Abstracts

Rationale: Large conductance, calcium-activated (BK-type) potassium channels have a specialized role as negative-feedback regulators of voltage-dependent calcium channels in many cell types. However in many neurons, calcium influx reduces excitability by activating other calcium-activated potassium channels that mediate spike frequency adaptation. In the dentate gyrus of the hippocampus the accessory beta4 subunit reduces BK channel activation during action potential firing. Knockout of the beta4 subunit causes seizures in mice. Our hypothesis is that BK channels can be pro-epileptic in dentate gryus granule cells by reducing a specific calcium influx pathway required for spike frequency adaptation.Methods: Here we study the mechanism by which calcium regulates excitability using patch clamp recording of dentate gyrus granule cells in mice brain slices. The contribution of various calcium influx channels and calcium release channels were evaluated using specific antagonists and observing their effect on spike frequency adaptation.Results: We find that beta4 subunit inhibition of BK channels allows increased calcium influx and recruitment of SK-type calcium-activated potassium channels. SK channels contribute to spike-frequency adaptation, reduce firing frequency and protect against seizures that otherwise occur in beta4 knockout mice. Utilizing pharmacology blockers, the combined contributions of N-type voltage-dependent calcium influx and calcium-induced calcium release through ryanodine receptors serve to activate SK channels and control firing frequency.Conclusions: These findings suggest that BK channel activation is antagonistic to calcium influx through N-type voltage-dependent calcium channels. Enhanced BK channel activation may be pro-epileptic by restricting calcium influx pathways to other calcium-activated potassium channels that control spike frequency