Targeting GABA_C Receptors Improves Post-Stroke Motor Recovery

• Main Authors: Petra S. van Nieuwenhuijzen, Kim Parker, Vivian Liao, Josh Houlton, Hye-Lim Kim, Graham A. R. Johnston, Jane R. Hanrahan, Mary Chebib, Andrew N. Clarkson
• Format: Article
• Language: English
• Published: MDPI AG 2021-03-01
• Series: Brain Sciences
• Subjects: photothrombotic stroke; tonic inhibition; motor behavior; GABA; GABA receptors; reactive astrogliosis
• Online Access: https://www.mdpi.com/2076-3425/11/3/315

Ischemic stroke remains a leading cause of disability worldwide, with limited treatment options available. This study investigates GABA_C receptors as novel pharmacological targets for stroke recovery. The expression of r1 and r2 mRNA in mice were determined in peri-infarct tissue following photothrombotic motor cortex stroke. (<i>R</i>)-4-amino-cyclopent-1-enyl butylphosphinic acid (<i>R</i>)-4-ACPBPA and (<i>S</i>)-4-ACPBPA were assessed using 2-elecotrode voltage electrophysiology in <i>Xenopus laevis</i> oocytes. Stroke mice were treated for 4 weeks with either vehicle, the α5-selective negative allosteric modulator, L655,708, or the r1/2 antagonists, (<i>R</i>)-4-ACPBPA and (<i>S</i>)-4-ACPBPA respectively from 3 days post-stroke. Infarct size and expression levels of GAT3 and reactive astrogliosis were determined using histochemistry and immunohistochemistry respectively, and motor function was assessed using both the grid-walking and cylinder tasks. After stroke, significant increases in r1 and r2 mRNAs were observed on day 3, with r2 showing a further increase on day 7. (<i>R</i>)- and (<i>S</i>)-4-ACPBPA are both potent antagonists at r2 and only weak inhibitors of α5β2γ2 receptors. Treatment with either L655,708, (<i>S</i>)-4-ACPBPA (r1/2 antagonist; 5 mM only), or (<i>R</i>)-4-ACPBPA (r2 antagonist; 2.5 and 5 mM) from 3 days after stroke resulted in a significant improvement in motor recovery on the grid-walking task, with L655,708 and (<i>R</i>)-4-ACPBPA also showing an improvement in the cylinder task. Infarct size was unaffected, and only (<i>R</i>)-4-ACPBPA significantly increased peri-infarct GAT3 expression and decreased the level of reactive astrogliosis. Importantly, inhibiting GABA_Creceptors affords significant improvement in motor function after stroke. Targeting the r-subunit could provide a novel delayed treatment option for stroke recovery.