Low frequency stimulation for seizure suppression: identification of optimal targets in the entorhinal-hippocampal circuit

Abstract

BackgroundMesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is a common form of drug-resistant focal epilepsy in adults. Treatment for pharmacoresistant patients remains a challenge, with deep brain stimulation (DBS) showing promise for alleviating intractable seizures. This study explores the efficacy of low-frequency stimulation (LFS) on specific neuronal targets within the entorhinal-hippocampal circuit in a mouse model of MTLE. Objective/HypothesisOur previous research demonstrated that LFS of the medial perforant path (MPP) fibers in the sclerotic hippocampus reduced seizures in epileptic mice. Here, we aimed to identify the critical neuronal population responsible for this antiepileptic effect by optogenetically stimulating presynaptic and postsynaptic compartments of the MPP-dentate granule cell (DGC) synapse at 1 Hz. We hypothesize that specific targets for LFS can differentially influence seizure activity depending on the cellular identity and location within or outside the seizure focus. MethodsWe utilized the intrahippocampal kainate (ihKA) mouse model of MTLE and targeted specific neural populations using Channelrhodopsin2 (ChR2) and stereotactic optic fiber implantation. We recorded intracranial neuronal activity from freely moving chronically epileptic mice with and without optogenetic LFS up to three hours. ResultsWe found that LFS of MPP fibers in the sclerotic hippocampus effectively suppressed epileptiform activity while stimulating principal cells in the MEC had no impact. Targeting DGCs in the sclerotic septal or non-sclerotic temporal hippocampus with LFS did not reduce seizure numbers but shortened the epileptiform bursts. ConclusionPresynaptic stimulation of the MPP-DGC synapse within the sclerotic hippocampus is critical for seizure suppression via LFS.