| Autor: |
Lie ME; 1 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.; 2 Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, New Zealand., Gowing EK; 2 Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, New Zealand., Johansen NB; 1 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Dalby NO; 1 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Thiesen L; 1 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Wellendorph P; 1 Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark., Clarkson AN; 2 Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, New Zealand.; 3 Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia. |
| Abstrakt: |
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 µM or 380 µM) 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. |
