The Role Astrocytic ASIC1a In The Pathogenesis Of Temporal Lobe Epilepsy

Epilepsy is the second most common neurological disease, which is charactered with the repeatability, unpredictability of onset and long-term drug treatment. Even with systematic and canonical antiepileptic therapy, about one third patients have poor seizure control and become refractory epilepsy, which is greatly suffered by, patients and their families. Therefore, finding the new therapy to cure epilepsy has been an important project in neurology. Now, most AEDs, which are mainly focused on seizure control, but barely effect on the reversal of the chronic epilepsy pathogenesis, fail to the cure of epilepsy. In this condition, finding new drugs focusing on epileptogenesis may bring new hope to the cure of epilepsy. Mounts of animal experiments and clinic specimen of epilepsy demonstrate that astrogliosis is a prominent change in the pathology of epileptogenesis. Our team previous study found that the expression of astrocytic ASIC1a(acid sensing ion channel 1a) is increased in chronic period, which is possibly related to the pathology of epileptogenesis, suggesting that astrocytic ASIC1 a plays a role in the pathology of epileptogenesis, and may be a potential target in epilepsy.ObjectiveTo investigate the role of astrocytic ASIC1 a in the epileptogenesis of mice temporal lobe model. MethodDesign recombined adeno-associated virus(r AAV), carrying sh RN A or ORF of acid sensing ion channel 1a(ASIC1a), under the control of astrocyte specific promoter GFAP(r AAV-GFAP-GFP-ASIC1a-sh RNA, r AAV-GFAP-ASIC1a-GFP). Bilateral intrahippocampal injection of virus interrupted the expression of ASIC1 a in astrocyte, regulating the expression of ASIC1 a in astrocyte, which is mean that downregulating the expression of wild-type and recovering the Asic1a-/-.We used male, 8 week age-matched, WT and Asic1a-/- congenic C57 background mice. Lithium and pilocarpine were injected intraperitoneal into the mice to construct temporal lobe epilepsy model. After 3 to 5 days, viral stereotactic injection and electrodes were performed. We observed the change of electroencephalogram(EEG) and behavior seizure in silent(12 to 19 days after model construction) and chronic(5 to 6 weeks after model construction) period, combined with the result of immunofluorescent staining, in the following 4 groups: WT interference group(downregulating the exopression of ASIC1a), WT control group, KO reconstruction group(recovering the expression of ASIC1a) and KO control group. Result1、Five weeks after viral stereotactic injection in hippocampus, more than 90% astrocytes express GFP.2、In the silent period of epilptogenesis, there was no different in the total seizure frequency, seizure score and average duration of spontaneous seizures(P>0.05). Besides, there were no differences in total EEG power between WT interference group and WT control group, KO reconstruction group and KO control group, KO reconstruction group and WT interference group, respectively(P>0.05).3、In chronic period of epileptogenesis, WT control group had most seizure numbers, while KO control group the least. WT interference group had less seizure times than WT control group(P<0.05), and KO reconstruction group had more seizure times than KO control group(P<0.05). There were no difference between each group in seizure score and average duration of spontaneous seizure(P>0.05). Meanwhile, WT interference group had significantly lower total EEG power than WT control group(P<0.001). KO control group had lower total EEG power than KO reconstruction group(P<0.001). WT interference group had lower total EEG power than KO reconstruction group(P<0.001). ConclusionIn temporal lobe epilepsy mice model, specific inhibition of astrocytic ASIC1 a expression significantly reduced the number of chronic spontaneous seizures and alleviated the degree of EEG abnormal discharge. This suggests that astrocytic ASIC1 a may be a new target for epilepsy treatment.