title: Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice.
abstract: A deeper understanding of post-stroke plasticity is critical to devise more effective pharmacological and rehabilitative treatments. The GABAergic system is one of the key modulators of neuronal plasticity, and plays an important role in the control of "critical periods" during brain development. Here, we report a key role for GABAergic inhibition in functional restoration following ischemia in the adult mouse forelimb motor cortex. After stroke, the majority of cortical sites in peri-infarct areas evoked simultaneous movements of forelimb, hindlimb and tail, consistent with a loss of inhibitory signalling. Accordingly, we found a delayed decrease in several GABAergic markers that accompanied cortical reorganization. To test whether reductions in GABAergic signalling were causally involved in motor improvements, we treated animals during an early post-stroke period with a benzodiazepine inverse agonist, which impairs GABAAreceptor function. We found that hampering GABAAsignalling led to significant restoration of function in general motor tests (i.e., gridwalk and pellet reaching tasks), with no significant impact on the kinematics of reaching movements. Improvements were persistent as they remained detectable about three weeks after treatment. These data demonstrate a key role for GABAergic inhibition in limiting motor improvements after cortical stroke.
authors.affiliation: Scuola Normale Superiore, 56126, Pisa, Italy.|CNR Neuroscience Institute, 56124, Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Alia
authors.affiliation: CNR Neuroscience Institute, 56124, Pisa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Spalletti
authors.affiliation: The BioRobotics Institute Scuola Superiore Sant'Anna, 56025, Pontedera (PI), Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Lai
authors.affiliation: The BioRobotics Institute Scuola Superiore Sant'Anna, 56025, Pontedera (PI), Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Panarese
authors.affiliation: The BioRobotics Institute Scuola Superiore Sant'Anna, 56025, Pontedera (PI), Italy.|Ecole Polytechnique Federale de Lausanne (EPFL), Bertarelli Foundation Chair in Translational NeuroEngineering Laboratory, Center for Neuroprosthetics and Institute of Bioengineering, CH-1015 Lausanne, Switzerland.
authors.forename: Silvestro
authors.initials: S
authors.lastname: Micera
authors.affiliation: CNR Neuroscience Institute, 56124, Pisa, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Caleo
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005552:Forelimb / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009473:Neuronal Plasticity / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058785:GABA-A Receptor Agonists