title: Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target.
abstract: Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of α1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery.
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA tbliss1@stanford.edu gsteinberg@stanford.edu.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hiu
authors.affiliation: 3 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA tbliss1@stanford.edu gsteinberg@stanford.edu.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Farzampour
authors.affiliation: 3 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA 4 Gladstone Institute of Neurological Disease and University of California, San Francisco San Francisco, CA USA.
authors.forename: Jeanne T
authors.initials: JT
authors.lastname: Paz
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA.
authors.forename: Eric Hou Jen
authors.initials: EH
authors.lastname: Wang
authors.affiliation: 3 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
authors.forename: Corrine
authors.initials: C
authors.lastname: Badgely
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Olson
authors.affiliation: 5 Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
authors.forename: Kristina D
authors.initials: KD
authors.lastname: Micheva
authors.affiliation: 5 Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Wang
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA 6 KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology; VIB - Vesalius Research Center University Hospitals Leuven, Department of Neurology, B-3000 Leuven, Belgium.
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA.
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Tran
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nishiyama
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA.
authors.forename: Xibin
authors.initials: X
authors.lastname: Liang
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Hamilton
authors.affiliation: 5 Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: O'Rourke
authors.affiliation: 5 Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smith
authors.affiliation: 3 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Huguenard
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA.
authors.forename: Tonya M
authors.initials: TM
authors.lastname: Bliss
authors.affiliation: 1 Department of Neurosurgery, Stanford University, Stanford, CA, USA 2 Stanford Stroke Centre, Palo Alto, CA 94304, USA 3 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA tbliss1@stanford.edu gsteinberg@stanford.edu.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Steinberg
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000639:trends; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D011725:Pyridines / Q000008:administration & dosage*; D011963:Receptors, GABA-A / Q000502:physiology*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000077334:Zolpidem
chemical_list: D058785:GABA-A Receptor Agonists; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem
keywords: brain repair; phasic GABA; stroke; zolpidem