Electrical stimulation of the ventral hippocampal commissure delays experimental epilepsy and is associated with altered microRNA expression

Brain Stimul. Nov-Dec 2019;12(6):1390-1401. doi: 10.1016/j.brs.2019.06.009. Epub 2019 Jun 7.

Abstract

Background: Up to 80% of mesial temporal lobe epilepsy patients with hippocampal sclerosis (mTLE-HS) are resistant to pharmacological treatment, often necessitating surgical resection. Deep brain stimulation (DBS) has emerged as an alternative treatment for patients who do not qualify for resective brain surgery. Brain stimulation may also exert disease-modifying effects, and noncoding microRNAs have recently been proposed to shape the gene expression landscape in epilepsy.

Objective: We compared the effect of DBS of 4 different hippocampal target regions on epileptogenesis and manifest epilepsy in a rat model of mTLE-HS. To explore mechanisms, we profiled the effect of the most effective DBS paradigm on hippocampal microRNA levels.

Methods: MTLE-HS was induced by electrical stimulation of the perforant pathway (PP) in rats. This paradigm leads to spontaneous seizures within 4 weeks. We investigated DBS of 4 targets: PP, fimbria fornix (FF) formation, dentate gyrus (DG) and ventral hippocampal commissure (VHC). We applied both high- (130 Hz) and low-frequency (5 Hz or 1 Hz) stimulation. Functional microRNAs were identified in the hippocampus immediately after VHC-DBS and after a 97-day recording period by sequencing small RNAs bound to Argonaute-2, a component of the miRNA silencing complex.

Results: Low frequency DBS of the VHC significantly delayed the occurrence of the first spontaneous recurrent seizure in the PPS model by ∼300%, from 19 to 56 days. No other stimulation regime altered the latency phase. Upregulation of 5 microRNAs during epileptogenesis was suppressed by VHC-stimulation.

Conclusion: We conclude that DBS of the VHC delays epilepsy in the PPS model in rats and is associated with differential regulation of several miRNAs. Additional studies are required to determine whether VHC-regulated miRNAs serve causal roles in the anti-epileptogenic effects of this DBS model.

Keywords: Deep brain stimulation; Hippocampal sclerosis; Mesial temporal lobe epilepsy; Ventral hippocampal commissure; microRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Deep Brain Stimulation / methods*
  • Epilepsy, Temporal Lobe / genetics
  • Epilepsy, Temporal Lobe / metabolism*
  • Epilepsy, Temporal Lobe / therapy*
  • Fornix, Brain / metabolism*
  • Gene Expression
  • Male
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / genetics
  • Seizures / metabolism
  • Seizures / therapy

Substances

  • MicroRNAs