Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke
Open accessAbstract
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.
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In peri-infarct cortex of the lesioned hemisphere, tonic inhibition of layer 2/3 pyramidal neurons is present from 3-14 days after stroke and is mediated by extrasynaptic GABA_A receptors.
“In the peri-infarct cortex of the lesioned hemisphere, tonic inhibition of layer 2/3 pyramidal neurons was present from 3–14 days after stroke and was mediated by extrasynaptic GABAA receptors.74”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [74]
A pharmacological antagonist of GABA_A receptor α5 subunit prevented excessive inhibition, as did genetic deletion of GABA_A receptor α5 or δ subunits, and improved stroke recovery.
“A pharmacological antagonist of the GABAA receptor α5 subunit prevented the excessive inhibition, as did genetic deletion of the GABAA receptor α5 or δ subunits, and improved stroke recovery.74”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [74]
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- Authors
- Clarkson, A. N., Huang, B. S., MacIsaac, S. E., Mody, I., & Carmichael, S. T.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Carmichael, S. Thomas
- Venue
- Nature
- Published
- 2010-11
- Volume
- 468
- Issue
- 7321
- Pages
- 305-309
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3058798
- OpenAlex
- W2099631417
- Cited by
- 869
- References
- 41
- Citations by year
- 2026: 35 · 2025: 49 · 2024: 51 · 2023: 48 · 2022: 51 · 2021: 60 · 2020: 64 · 2019: 70 · 2018: 53 · 2017: 69 · 2016: 48 · 2015: 57 · 2014: 77 · 2013: 53 · 2012: 42
- FWCI
- 17.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R37NS030549, R01NS030549, NS30549)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- stroke, functional recovery, extrasynaptic GABAA receptors, tonic inhibition, GABA transporters, GAT-3, peri-infarct zone, alpha5 subunit, benzodiazepine inverse agonist, motor recovery, neuroplasticity, brain injury, therapeutic target
- MeSH terms
- Animals, Benzodiazepines, Cerebral Infarction, Disease Models, Animal, gamma-Aminobutyric Acid, Imidazoles, Male, Membrane Potentials, Mice, Inbred C57BL, Motor Cortex, Neuronal Plasticity, Synapses, Time Factors, Receptors, GABA, GABA Antagonists, Recovery of Function, Stroke, GABA Plasma Membrane Transport Proteins, Mice, Drug Inverse Agonism
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