Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy.

Enya Paschen,Marlene Bartos,Ute Häussler,Catarina Orcinha,Katharina Heining,Claudio Elgueta,Diego M Vieira,Philipp Janz,Piret Kleis,Ulrich Egert,Carola A Haas

doi:10.7554/elife.54518

Abstract

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal, pharmacoresistant epilepsy in adults and is often associated with hippocampal sclerosis. Here, we established the efficacy of optogenetic and electrical low-frequency stimulation (LFS) in interfering with seizure generation in a mouse model of MTLE. Specifically, we applied LFS in the sclerotic hippocampus to study the effects on spontaneous subclinical and evoked generalized seizures. We found that stimulation at 1 Hz for 1 hr resulted in an almost complete suppression of spontaneous seizures in both hippocampi. This seizure-suppressive action during daily stimulation remained stable over several weeks. Furthermore, LFS for 30 min before a pro-convulsive stimulus successfully prevented seizure generalization. Finally, acute slice experiments revealed a reduced efficacy of perforant path transmission onto granule cells upon LFS. Taken together, our results suggest that hippocampal LFS constitutes a promising approach for seizure control in MTLE.

Highlights

Mesial temporal lobe epilepsy (MTLE) represents the most common form of acquired epilepsy in adults
Quantitative analysis of granule cell dispersion (GCD) in NeuN-stained sections revealed that the volume of the dispersed granule cell layer (GCL) was comparable between 20 and 15 mM KA but significantly smaller in the 10 mM KA group (Figure 2B, 10 mM: 0.24 ± 0.08 mm3; 15 mM: 1.56 ± 0.16 mm3; 20 mM: 1.52 ± 0.11 mm3, 10 mM vs 15 mM and vs. 20 mM p
To investigate whether optogenetic LFS (oLFS) decreases the excitability of dentate granule cells (DGCs) at the single-cell level, we studied their intrinsic properties and the synaptic strength of entorhinal inputs in acute slices obtained from chronically epileptic mice

Summary

Introduction

Mesial temporal lobe epilepsy (MTLE) represents the most common form of acquired epilepsy in adults. Optogenetic stimulation offers cell- or pathway-specific modulation of neuronal activity and has been successfully applied to alleviate seizure burden in several rodent MTLE models (KrookMagnuson and Soltesz, 2015; Zhao et al, 2015). These optogenetic approaches targeting the hippocampus were either based on the inhibition of excitatory neurons or on the recruitment of inhibitory interneurons (Kim et al, 2020; Kokaia et al, 2013; Krook-Magnuson et al, 2013; Ladas et al, 2015; Ledri et al, 2014; Lu et al, 2016). We present evidence that LFS is highly effective in preventing both subclinical epileptiform activity and behavioral seizures in experimental MTLE with severe hippocampal sclerosis

Results

Discussion

Materials and methods

Funding Funder Deutsche Forschungsgemeinschaft