Activation of SK channels inhibits epileptiform bursting in hippocampal CA3 neurons

The role of calcium-activated potassium channels in the regulation of neuronal hyperexcitability, as in epilepsy, is unclear. To examine this issue, we have used the acute hippocampal slice model of epileptiform activity to investigate the effects of an enhancer of SK channel activity, 1-ethyl-benzimidazolinone (EBIO). That EBIO is an SK channel modulator was confirmed by its potentiation of hSK1, hSK2, hSK3 and hIK currents (EC50 values in the range of 130-870 μM) and its apamin (1 μM) sensitive reduction of the number of action potentials fired in CA3 pyramidal neurons in response to a depolarizing current step. In addition, while EBIO did not significantly affect electrically evoked glutamatergic synaptic transmission, it did inhibit epileptiform activity (IC50 values in the range of 150-325 μM) induced by (1) modifying the extracellular ionic environment by removing extracellular Mg2+ or elevating extracellular K+ from 3.0 to 8.5 mM and (2) disinhibiting the slice using 3 mM pentylenetetrazol or combined application of 10 μM gabazine and 10 μM CGP55845. Furthermore, its inhibitory effect in the full disinhibition model of epileptiform activity (10 μM gabazine + 10 μM CGP55845) was occluded by the SK channel blocker apamin (300 nM-1 μM) which in its own right increased the duration and reduced the frequency of individual epileptiform bursts. In conclusion, compounds that enhance the activation of small conductance Ca2+-activated K+ channels are effective inhibitors of epileptiform activity in vitro.