Role And Mechanism Of Acid-sensing Ion Channel 1a Underlying Interneuron Regulation And Its Involvement In Epilepsy

Background and objective:As one of the most common chronic neurological disorders,epilepsy is caused by the highly synchronized abnormal discharge of neurons that is triggered by a variety of reasons.Antiepileptic drugs(AEDs)are currently the mainstay of epilepsy treatment.However,there are still nearly 30%of patients with symptoms that can not be controlled.In recent years,a number of studies using animal or cell epilepsy models have shown that acid-sensing ion channel la(ASICla)plays an important role in the generation,propagation and termination of epilepsy.Some suggest that ASIC la promotes the development of chronic epilepsy,while the others suggest that ASIC la favors the termination of epileptic seizure activity.Therefore,in this study we explored the role and mechanism of ASIC1a underlying interneuron regulation and its involvement in epilepsy based on surgical specimens,hoping to provide new ideas and targets for the epilepsy treatment.Materials and methods:All procedures and experiments were approved by the Ethics Committee of the Second Affiliated hospital of Zhejiang University School of Medicine,where informed consents were obtained for the use of brain tissue and medical records for research purposes.Six patients with idiopathic temporal lobe epilepsy(TLE)and three patients with acquired epilepsy were enrolled as the epilepsy group,while four patients with trauma or brain tumor were enrolled as the control group.The expression of ASIC1a protein was tested by Western blotting.An epilepsy human brain slice model was successfully established for whole-cell patch clamp study.By reducing the pH of brain slice perfusion fluid to activate or adding PcTxl to specifically block the ASIC1a channel,we studied the effect of ASIC1a on the eletrophysiological properties of inhibitory intemeurons in epilepsy tissue.Results:(1)The expression of ASIC1a protein in the epilepsy brain tissue was significantly lower than that in the normal brain tissue.The expression of ASIC1a protein between idiopathic and acquired epilepsy was different,but showed no statistical significance.(2)In temporal lobe epilepsy tissue,there was a decrease in the sensitivity of FS-interneuron to current stimulation after adding the ASIC la-specific inhibitor PcTxl.(3)Blocking ASIC1a channel significantly reduced the frequency of action potentials of FS-interneuron in human brain tissue.However,this effect was partially impaired in temporal lobe epilepsy.(4)Blocking ASIC1a channel significantly elevated the threshold of FS-interneuron’s action potentials,but had no effects on its amplitude or post-hyper polarization.(5)ASIC1a significantly increased the release of spontaneous action potentials of FS-intemeuron in temporal lobe epilepsy.Conclusion:Compared with the normal brain tissue,there was a significant down-regulation of ASIC1a protein in epilepsy.In temporal lobe epilepsy,ASIC1a had not only up-regulated the sensitivity,intrinsic excitability and spontaneous discharges of FS-interneuron,but also lowered the threshold of FS-interneuron’s action potentials.Our study suggests that the down-regulation of ASIC1a and its dysfunction in inhibitory neurons may be related to the development of epilepsy,and the activation of ASIC1a underlying interneuron may contribute to the termination of seizures.