Low-frequency Stimulation at the Subiculum Prevents Extensive Secondary Epileptogenesis in Temporal Lobe Epilepsy
Yujia Shen1,2 · Yiwei Gong1,2 · Xiaoli Da1 · Shajing Gao1 · Shuo Zhang1,4 · Minjuan Sun1 · Yuanzhi Yang1 · Xiaoyun Qiu1 · Menghan Li1 · Yang Zheng1,3 · Fan Fei1,2 · Yi Wang1,2 · Zhong Chen1,2 · Cenglin Xu11 Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310053, China
2 Institute of Pharmacology and Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
3 Department of Neurology, First Afliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310003, China
4 Department of Pharmacy, The First Afliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310003, China
Abstract
Secondary epileptogenesis is characterized by increased epileptic susceptibility and a tendency to generate epileptiform activities outside the primary focus. It is one of the major resultants of pharmacoresistance and failure of surgical outcomes in epilepsy, but still lacks effective treatments. Here, we aimed to test the effects of low-frequency stimulation (LFS) at the subiculum for secondary epileptogenesis in a mouse model. Here, secondary epileptogenesis was simulated at regions both contralateral and ipsilateral to the primary focus by applying successive kindling stimuli. Mice kindled at the right CA3 showed higher seizure susceptibilities at both the contralateral CA3 and the ipsilateral entorhinal cortex and had accelerated kindling processes compared with naive mice. LFS at the ipsilateral subiculum during the primary kindling progress at the right CA3 effectively prevented secondary epileptogenesis at both the contralateral CA3 and the ipsilateral entorhinal cortex, characterized by decreased seizure susceptibilities and a retarded kindling process at those secondary foci. Only application along with the primary epileptogenesis was effective. Notably, the effects of LFS on secondary epileptogenesis were associated with its inhibitory effect at the secondary focus through interfering with the enhancement of synaptic connections between the primary and secondary foci. These results imply that LFS at the subiculum is an effective preventive strategy for extensive secondary epileptogenesis in temporal lobe epilepsy and present the subiculum as a target with potential translational importance.
Keywords
Secondary epileptogenesis; Low-frequency stimulation; Subiculum; Temporal lobe epilepsy
