%0 Journal Article
%T GAT3 selective substrate l
%A Andrew N Clarkson
%A Emma K Gowing
%A Louise Thiesen
%A Maria EK Lie
%A Nils Ole Dalby
%A Nina B Johansen
%A Petrine Wellendorph
%J Journal of Cerebral Blood Flow & Metabolism
%@ 1559-7016
%D 2019
%R 10.1177/0271678X17744123
%X Ischemic stroke triggers an elevation in tonic GABA inhibition that impairs the ability of the brain to form new structural and functional cortical circuits required for recovery. This stroke-induced increase in tonic inhibition is caused by impaired GABA uptake via the glial GABA transporter GAT3, highlighting GAT3 as a novel target in stroke recovery. Using a photothrombotic stroke mouse model, we show that GAT3 protein levels are decreased in peri-infarct tissue from 6£¿h to 42 days post-stroke. Prior studies have shown that GAT substrates can increase GAT surface expression. Therefore, we aimed to assess whether the GAT3 substrate, L-isoserine, could increase post-stroke functional recovery. L-Isoserine (38£¿¦ÌM or 380£¿¦ÌM) administered directly into the infarct from day 5 to 32 post-stroke, significantly increased motor performance in the grid-walking and cylinder tasks in a concentration-dependent manner, without affecting infarct volumes. Additionally, L-isoserine induced a lasting increase in GAT3 expression in peri-infarct regions accompanied by a small decrease in GFAP expression. This study is the first to show that a GAT3 substrate can increase GAT3 expression and functional recovery after focal ischemic stroke following a delayed long-term treatment. We propose that enhancing GAT3-mediated uptake dampens tonic inhibition and promotes functional recovery after stroke
%K Photothrombotic stroke
%K GAT3 substrate inhibitor
%K L-isoserine
%K tonic inhibition
%K functional recovery
%U https://journals.sagepub.com/doi/full/10.1177/0271678X17744123