Low dose of levetiracetam counteracts amyloid β-induced alterations of hippocampal gamma oscillations by restoring fast-spiking interneuron activity

Abstract

Alzheimer's disease (AD) is characterized at an early stage by memory alterations that worsen during the development of the disease. Several clinical trials in phase 3 have failed despite being able to counteract classical AD-related alterations, possibly because of the lack of recovery of the regular neuronal network activity essential for memory including low gamma oscillations (γ-Osc). Nowadays, Levetiracetam (LEV), an SV2A modulator approved for epilepsy, is being used in trials with AD patients without further support for neurophysiological relevant effects on restoring the normal function of hippocampal neuronal network activity. Using concomitant recordings of local field potential γ-Osc and patch-clamp recordings of fast-spiking interneurons (FS-IN) on hippocampal slices of WT and AppNL-G-F AD animals, we found that LEV restores the power and rhythmicity of γ-Osc previously reduced by acute application of amyloid-β on WT hippocampal slices, this effect is accompanied by the recovery of the synchronicity in the firing of FS-IN. In addition, we found that LEV counteracts the hippocampal γ-Osc alterations in the early prodromal stage of the disease in AppNL-G-F mice by recovering the rhythmicity of γ-Osc and the synchronicity in the firing of FS-IN. Altogether the results show that the precise modulation of neuronal circuits with LEV is a promising strategy to counteract early-stage alterations in hippocampal activity by modulating FS-IN in a memory-relevant neuronal network state like γ-Osc.