Editors' ChoiceNeuroscience

Reducing Inhibition Can Enhance Recovery

Science Signaling  16 Nov 2010:
Vol. 3, Issue 148, pp. ec348
DOI: 10.1126/scisignal.3148ec348

Plastic changes in the peri-infarct zone adjacent to the damaged region have been implicated in functional recovery from the often devastating consequences of ischemic stroke. Noting that the inhibitory neurotransmitter GABA (γ-aminobutyric acid) has been implicated in cortical plasticity during development, Clarkson et al. investigated GABA signaling in peri-infarct mouse cortex after stroke. Whole-cell voltage clamp recordings of peri-infarct regions of mouse brain slices prepared 3 days to 2 weeks after a stroke revealed increased tonic inhibition mediated through extrasynaptic GABAA receptors. The concentration of GABA to which these receptors are exposed—and thereby the degree of tonic inhibition—depends on the activity of GABA transporters (GATs); pharmacological analysis revealed decreased function of GAT-3/GAT-4 (mouse GAT-4, a homolog of human GAT-3), consistent with decreased abundance as identified by Western analysis. L655,708, an antagonist of the α5-GABAA receptor, reduced tonic inhibition in vitro and enhanced recovery of motor function when administered in vivo starting 3 days after a stroke. Mice lacking α5-subunit–containing GABAA receptors showed better motor recovery after a stroke than did wild-type mice, as did, albeit to a lesser extent, mice lacking δ-subunit–containing GABAA receptors. Treatment with the combination of L655,708 and picrotoxin, which acts on both synaptic and extrasynaptic GABAA receptors, led to a worse long-term outcome (28 to 42 days after stroke) than did treatment with L655,708 alone, and starting L655,708 treatment at the time of stroke increased stroke volume. The authors thus conclude that targeting tonic GABA-mediated inhibition in the appropriate time frame may provide a therapeutic strategy to enhance recovery from stroke. Staley provides thoughtful commentary.

A. N. Clarkson, B. S. Huang, S. E. MacIsaac, I. Mody, S. T. Carmichael, Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468, 305–309 (2010). [PubMed]

K. Staley, Recovery inhibitors under attack. Nature 468, 176–177 (2010). [PubMed]