Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke

Stroke is a leading cause of disability because of the brain's limited capacity for recovery. The functional recovery that does occur derives in part from the transfer of brain function to the tissue bordering the stroke site. A study in a mouse model shows that stroke reduces excitation in neurons adjacent to the stroke site by impairing transport of GABA, leading to a build-up of this inhibitory neurotransmitter. Genetic or pharmacological blockade of extrasynaptic GABAA receptors improves behavioural recovery. Critically, the treatment remains successful when there is a delay between stroke and therapy. This work identifies novel pharmacological targets for neural recovery after stroke and possibly other brain injuries. Following a stroke, there is generally limited functional recovery, but plasticity in adjacent intact areas may be critical to rehabilitation. These authors report that tonic GABAA inhibition is elevated in cortex immediately surrounding the stroke site. Furthermore, genetically or pharmacologically reducing tonic GABAA receptor signalling leads to improved functional and motor recovery in a mouse model of stroke, suggesting that this could be a new pharmacological target for stroke therapy. Stroke is a leading cause of disability, but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage—the peri-infarct zone—is critical for rehabilitation, as it shows heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas1,2,3. Thus, understanding the neuronal properties constraining this plasticity is important for the development of new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABAA receptors and is caused by an impairment in GABA (γ-aminobutyric acid) transporter (GAT-3/GAT-4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for α5-subunit-containing extrasynaptic GABAA receptors at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of α5- or δ-subunit-containing GABAA receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABAA receptor function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.