Knockdown SIK3 in hippocampal CA1 decreases seizure susceptibility in mice

Abstract The imbalance between excitation and inhibition is an important cause of epilepsy. It has been found that SIK1 gene mutation can cause epilepsy. In this study, we first found that the expression of SIK3 is increased after epilepsy. Furthermore, the role of SIK3 in epilepsy is explored. In the cultured hippocampal neurons, we used Pterosin B, a selective SIK3 inhibitor, that could inhibit epileptiform discharges induced by the convulsant drug cyclothiazide (a positive allosteric modulator of AMPA receptors, CTZ). Knockdown SIK3 could also inhibit epileptiform discharges and increase the amplitude of mIPSC currents. In mice, knockdown SIK3 could reduce the epilepsy susceptibility in pentylenetetrazole (a GABAA receptor antagonist, PTZ) acute kindling experiment and increase the expression of GABAA receptor α1. In conclusion, our results suggest that blockade or knockdown SIK3 can inhibit epileptiform discharges, and SIK3 has the potential to be a novel target for epilepsy treatment.