P71. MicroRNA regulation in deep brain stimulation of different targets for epilepsy

Abstract

Rationale Epilepsy is a common neurological disorder with an incidence of 50.4 per 100,000 per year ( Ngugi et al., 2011 ). Up to 80% of mesial temporal lobe epilepsy (mTLE) patients are resistant to pharmacological treatment ( Semah et al., 1998 ). Many of them do not qualify for resective brain surgery. For these patients, an alternative treatment is deep brain stimulation (DBS). In epilepsy, different protocols for DBS have been tested but until now the mechanisms of DBS are not fully understood and the best protocol remains to be evaluated. MicroRNAs (miRNAs) are small, single stranded RNAs, which regulate protein synthesis on mRNA level. Various miRNAs have been found to be regulated in epilepsy, and regulation of miRNAs after DBS has been shown in Parkinson’s disease patients ( Soreq et al., 2013 ). We compared different targets and frequencies of DBS in a rat model of mTLE to identify a paradigm that inhibits epileptogenesis. Furthermore, we investigated miRNA regulation after DBS with the most effective paradigm. Methods We used the rat perforant pathways stimulation (PPS) model of mTLE ( Norwood et al., 2010 ). Thereby, stimulation electrodes are implanted into the PP and recording electrodes are implanted into the dentate gyrus (DG). After one week of recovery, rats are stimulated on two days for 30 min and on the third day for 8 h. This treatment leads to spontaneous seizures 12–34 days after stimulation. We investigated DBS of four different targets: the PP, the fimbria fornix formation (FF), the DG and the ventral hippocampal commissure (VHC); for one or two weeks starting one day after the 8 h stimulation, using three different stimulation paradigms: 130 Hz and 0.1 V, 5 Hz and 2 V or 1 V and 1 Hz. We furthermore analyzed miRNA expression in the hippocampus immediately after DBS and after a 97-day recording period. Thereafter, sequencing of active miRNAs was performed and compared to control rats which were not treated with DBS. Results A two-week DBS of the VHC with 1 Hz and 1 V significantly prolonged the latency period in the PPS model from 19 to 56 days. 8 microRNAs were significantly changed directly after DBS. Several miRNAs were changed in the control group after 97 days but showed no changes in expression in the DBS-treated group. These are potential candidates for an in vivo manipulation to inhibit epileptogenesis.