The excessive tonic inhibition of the peri-infarct cortex depresses low gamma rhythm power during post-stroke recovery

Abstract

The cortex immediately surrounding a brain ischemic lesion, the peri-infarct cortex, harbors a large part of the potential to recover lost functions. However, our understanding of the neurophysiological conditions in which synaptic plasticity operates, remains limited. Here we hypothesized that the chronic imbalance between excitation and inhibition of the peri-infarct cortex prevents the normalization of the gamma rhythm, a waveband of neural oscillations thought to orchestrate action potential trafficking. Probing the local field potential activity of the forelimb primary sensory cortex (S1FL) located in the peri-infarct cortex of male adult mice, we found a constant, deep reduction of low-gamma oscillation power (L-gamma; 30-50 Hz) precisely during the critical time window for recovery (1 to 3 weeks after stroke). The collapse of L-gamma power negatively corelated with behavioral progress in affected forelimb use. Mapping astrocyte reactivity and GABA-like immunoreactivity in the peri-infarct cortex revealed a parallel high signal, which gradually increased when approaching the lesion. Increasing tonic inhibition with local infusion of GABA or by blocking its recapture reduced L-gamma oscillation power in a magnitude similar to stroke. Conversely, the negative allosteric modulation of tonic GABA conductance using L655,708 or the gliopeptide ODN rescued the L-gamma power of the peri-infarct cortex. Altogether the present data point-out that the chronic excess of ambient GABA in the peri-infarct cortex limits the generation of L-gamma oscillations in the repairing cortex and suggests that rehabilitative interventions aimed at normalizing low-gamma power within the critical period of stroke recovery could optimize the restitution of lost functions.

Significance Statement After a stroke, the recovery of lost motor function depends on the reorganization of surviving neural networks. However, the excitation/inhibition balance in the repairing area is suboptimal as it leans excessively towards inhibition. In this work, using an in vivo approach, we demonstrate here that this imbalance, occurring during the critical window for recovery, leads to the collapse of gamma oscillations, a crucial cerebral rhythm for organizing neural communication. This study reinforces the concept of timely therapeutic interventions aimed at correcting the pathological oscillatory regimen of stroke recovery to enhance plasticity.