The authors examined the neuronal excitability of the peri-infarct cortex in a photothrombotic mouse model of focal stroke. They measured an increase in the GABA type A (GABAA) receptor-mediated tonic inhibition in these mice after stroke compared with sham controls, and the inhibition remained raised for 3–14 days. As GABAergic signalling is crucial in regulating normal cortical plasticity, it might have a similar role after stroke.
So, if excessive tonic inhibition constrains neuronal plasticity in the peri-infarct zone, does reducing this inhibition improve functional recovery? To address this question, the authors used L655,708 — a specific inverse agonist of α5-containing GABAA receptors that, together with δ-containing GABAA receptors, mediates tonic inhibition. Administration of this drug to the mice 3 days after stroke led to decreased tonic inhibition in post-stroke neurons compared with control neurons at day 7, which translated into improved forelimb motor control. Recovery from stroke was also tested in transgenic mice lacking either α5-GABAA or δ-GABAA receptors. The Gabra5−/− mice showed better motor recovery from stroke than control wild-type mice, a similar recovery to that seen in the drug-treated wild-type animals. Gabrad−/− mice also showed improvement in motor function, but less so than the Gabra5−/− mice. When L655,708 was administered to the Gabrad−/− mice, an even greater recovery was observed.
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