Reducing excessive GABAergic tonic inhibition promotes post-stroke functional recovery

By A. Clarkson, Ben S. Huang, Sarah E. Macisaac, István Módy, S. Carmichael. Nature, 2010

833 citations recorded by the source corpus.

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 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.

Subfields: Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/7ef849bd19f947ee23a7c3da086d133ada298f85

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In Cellular and Molecular Neuroscience

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Citations in the corpus

Inhibitory Plasticity Dictates the Sign of Plasticity at Excitatory Synapses (2014, background): “…Richards et al., 2010; House et al., 2011; Chen et al., 2012), circuit excitability (Ben-Ari, 2006; Fritschy, 2008; Carvalho and Buonomano, 2009; Clarkson et al., 2010), learning (Kano, 1995; Fritschy and Brünig, 2003; Ruediger et al., 2011), and sensory processing (Cardin et al., 2009;…”
The Role of GABA in Human Motor Learning (2011, positive): “anodal tDCS, that decrease GABA in a localized region in conjunction with rehabilitation in the context of stroke, in line with recent findings in an animal model [21].”
Extrasynaptic GABAA receptors: Their function in the CNS and implications for disease (2012, background): “As our recent findings (Clarkson et al., 2010) indicate, mechanisms involving an enhanced tonic inhibition that impede the functional plasticity of the adult brain in learning andmemory, such as those found in mice lacking a5-GABAARs or animals treated with a negative allosteric modulator of a5-GABA”
Neuroplasticity subserving motor skill learning (2011, positive): “…animals, yet possible links between these findings and demonstrations of structural plasticity in humans are, to date, still speculative; however, they show clear translational value in understanding motor skill learning after brain lesions (Clarkson et al., 2010, 2011; Li et al., 2010).”
Astrocyte reactivity and reactive astrogliosis: costs and benefits. (2014, background): “In mouse models, pharmacological treatment that blocks GABA binding to its receptors, when provided at the right time after stroke, results in a faster recovery of function (48).”