Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke
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TLDR
This work shows that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone, and identifies new pharmacological targets that provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.Abstract:
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 areas. 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 GABA(A) 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 GABA(A) 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 GABA(A) receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABA(A) 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.read more
Citations
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