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Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target


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Title: Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target
Authors: Hiu, Takeshi / Farzampour, Zoya / Paz, Jeanne T. / Wang, Eric Hou Jen / Badgely, Corrine / Olson, Andrew / Micheva, Kristina D. / Wang, Gordon / Lemmens, Robin / Tran, Kevin V. / Nishiyama, Yasuhiro / Liang, Xibin / Hamilton, Scott A. / O’Rourke, Nancy / Smith, Stephen J. / Huguenard, John R. / Bliss, Tonya M. / Steinberg, Gary K.
Issue Date: Feb-2016
Publisher: Oxford University Press
Citation: Brain, 139(2), pp.468-480; 2016
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.
Keywords: stroke / phasic GABA / brain repair / zolpidem
URI: http://hdl.handle.net/10069/39892
ISSN: 00068950
DOI: 10.1093/brain/awv360
Rights: © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Type: Journal Article
Text Version: publisher
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/39892

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