Single KATP Channel Opening in Response to Action Potential Firing in Mouse Dentate Granule Neurons

ATP-sensitive potassium channels (K-ATP channels) are important sensors of cellular metabolic state that link metabolism and excitability in neuroendocrine cells, but their role in nonglucosensing central neurons is less well understood. To examine a possible role for K-ATP channels in modulating excitability in hippocampal circuits, we recorded the activity of single K-ATP channels in cell-attached patches of granule cells in the mouse dentate gyrus during bursts of action potentials generated by antidromic stimulation of the mossy fibers. Ensemble averages of the open probability (p(open)) of single K-ATP channels over repeated trials of stimulated spike activity showed a transient increase in p(open) in response to action potential firing. Channel currents were identified as K-ATP channels through blockade with glibenclamide and by comparison with recordings from Kir6.2 knock-out mice. The transient elevation in K-ATP p(open) may arise from submembrane ATP depletion by the Na+-K+ ATPase, as the pump blocker strophanthidin reduced the magnitude of the elevation. Both the steady-state and stimulus-elevated p(open) of the recorded channels were higher in the presence of the ketone body R-beta-hydroxybutyrate, consistent with earlier findings that ketone bodies can affect K-ATP activity. Using perforated-patch recording, we also found that K-ATP channels contribute to the slow afterhyperpolarization following an evoked burst of action potentials. We propose that activity-dependent opening of K-ATP channels may help granule cells act as a seizure gate in the hippocampus and that ketone-body-mediated augmentation of the activity-dependent opening could in part explain the effect of the ketogenic diet in reducing epileptic seizures.