Reducing excessive GABAergic tonic inhibition promotes post-stroke functional recovery

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 exhibits heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas1–3. Thus, understanding the neuronal properties constraining this plasticity is important to developing 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 GABA(A) receptors (GABA(A)Rs) and is caused by an impairment in GABA transporter (GAT-3/4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for the α5-subunit-containing extrasynaptic GABA(A)Rs 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 GABA(A)Rs responsible for tonic inhibition also proved beneficial for post-stroke recovery, consistent with the therapeutic potential of diminishing extrasynaptic GABA(A)R 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.