TRESK Channel Overexpression Alleviates Sustained Depolarization-Induced Shunting Inhibition And Modulates Epileptic Behavior

Epilepsy is one of serious chronic neurological diseases.At present,the mechanism of the development of epilepsy is far from being clarified.Spontaneous termination is an important feature of seizures,and it is of great clinical significance to reveal its potential cellular and molecular mechanisms for the treatment of epilepsy,especially refractory epilepsy.In our previous study,we found that TRESK channel mediates the sustained depolarization-induced shunting inhibition(DshI)in hippocampal CA3 pyramidal neurons,and that TRESK channel knockout aggravates epileptic behavior of mice treated with convulsants,suggesting that TRESK channel contributes to spontaneous termination of epileptic seizures.However,the intracellular signaling mechanism underlying DshI mediated by TRESK channel and whether increased expression of TRESK channels can alleviate epileptic seizures are unclear.In this study,we found that increasing intracellular calcium concentration could induce neuronal inhibition similar to the DshI in pyramidal neurons of hippocampal CA3 region,and inhibition of intracellular calcineurin could significantly inhibit DshI.Secondly,the overexpression of TRESK channel in the hippocampus could shorten the seizure duration of epileptic seizures,prolong the post-seizure inhitition period,and significantly reduce the severity of epileptic seizures.Finally,overexpression of TRESK channels did not change the basic excitability and inhibitory synaptic transmission of pyramidal neurons in CA1 region,it also didn’t affect the resting membrane potential and the threshold levels of action potential.Overexpression of TRESK could reduce the excitability and membrane input resistance of pyramidal neurons in hippocampal CA1 region,also could increase the threshold intensity of evoked action potential and enhance DshI.These results suggest that the sustained depolarization-induced shunting inhibition is mediated by the intracellular calcium-calcineurin-TRESK channel signal pathway,and the overexpression of TRESK channel may alleviate seizures by enhancing the sustained depolarization-induced shunting inhibition of neurons.Therefore,TRESK channel may become a new target for anti-epileptic drug.