Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke.
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.
Department of Neurology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA.
Andrew N
AN
Clarkson
Ben S
BS
Huang
Sarah E
SE
Macisaac
Istvan
I
Mody
S Thomas
ST
Carmichael
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D054314:Drug Inverse Agonism; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009044:Motor Cortex / Q000378:metabolism / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology*; D009473:Neuronal Plasticity / Q000502:physiology; D018079:Receptors, GABA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D007093:Imidazoles; C105490:L 655,708; D018079:Receptors, GABA; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid