TRESK Channel Mediates Depolarization-induced Shunting Inhibition (DShI) And Modulates Epileptic Activity

Epilepsy,as a severe chronic disorder of the brain,affects the people worldwide.Although medication for epilepsy gains great progress,approximately one-third of patients were poorly responsive.Most seizures are self-terminated.However,the underlying cellular mechanisms remain unclear.Here,we found that sustained depolarization of neuron decreased its excitability and the somatic response to glutamate and GABA.These decreases in neuronal excitability and somatic response to GABA were also observed after termination of ictal-like events induced by omitting extracellular Mg2+ from ACSF.Pharmacologically application of a series of blockers for Na+,K+and Ca2+ channels indicating that TRESK channel(TWIK-related spinal cord K+channel,KCNK18,a member of two-pore domain background potassium channel)was responsible for that.TRESK knockout attenuated the inhibition of somatic response to GABA induced by depolarization.Moreover,sustained depolarization increased the membrane conductance and it was also blocked by TRESK blockers and was attenuated by TRESK knockout.In addition,acute induction of status epilepsy by pilocarpine and kainic acid(KA)consistently increased TRESK mRNA expression within 2 weeks.TRESK knockout aggravated KA-induced seizure severity.Finally,TRESK knockout reduced post-ictal depression induced by PTZ.Together,our results identify a non-synaptic,but neuronal intrinsic short-term plasticity,termed depolarization-induced shunting inhibition(DShI)and this DShI is partially mediated by TRESK,suggesting TRESK could be a therapeutic target for epileptic treatment.