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

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 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.

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Figure 1: Increased tonic inhibition in peri-infarct cortex.
Figure 2: Impairment in GABA transport and effect of blocking α5-GABA A receptors after stroke.
Figure 3: Behavioural recovery after stroke with L655,708 treatment and in Gabra5 −/− and Gabrd −/− animals
Figure 4: Inflection point in L655,708 treatment effect on infarct size.

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Acknowledgements

I.M., A.N.C. and S.T.C. were supported by The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. S.T.C. was supported by the Larry L. Hillblom Foundation, I.M. was supported by the Coelho Endowment and National Institutes of Health/National Institute of Neurological Disorders and Stroke grant NS30549. This manuscript was completed partially during tenure of an American Heart Association Postdoctoral Fellowship, a Repatriation Fellowship from the New Zealand Neurological Foundation and the Sir Charles Hercus Fellowship from the Health Research Council of New Zealand (A.N.C.). We thank E. O. Mann, J. Chu, J. J. Overman, J. Zhong and R. M. Lazaro for discussion and assistance.

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A.N.C. performed the behavioural, histological and immunohistochemical studies; B.S.H. carried out the electrophysiological experiments; and S.E.M. performed the immunohistochemical and western blot work. A.N.C., B.S.H., I.M. and S.T.C. designed the experiments, analysed data, prepared figures and wrote the manuscript.

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Correspondence to S. Thomas Carmichael.

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Clarkson, A., Huang, B., MacIsaac, S. et al. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468, 305–309 (2010). https://doi.org/10.1038/nature09511

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