Introduction: Stroke is a major cause of disability yet pharmacotherapy targeting the recovery phase is lacking. Cortical circuit reorganization adjacent to the stroke site promotes recovery, elucidating mechanisms that promote this could lead to new therapeutics. Tonic neuronal inhibition, mediated by extrasynaptic GABAA receptors, inhibits post-stroke recovery. However, effects of phasic (synaptic) GABA signaling are unknown. Here we demonstrate that phasic GABA in the repair phase of stroke is beneficial for recovery.
Methods: 12-week-old C57BL/6J male mice were subjected to the distal middle cerebral artery occlusion model of ischemia. Array tomography analysis of synapses: tissue was removed from the peri-infarct cortex at 1 week or 1 month post-stroke, ribbons of serial ultrathin sections (70 nm) cut, stained with antibodies for synaptic markers, and analyzed to quantify GABAergic synapses. Whole-cell patch clamp recordings from acute neocortical brain slices were performed to evaluate GABA-mediated synaptic signaling in the peri-infarct cortex. Behavior was evaluated using the adhesive dot removal test. Zolpidem, or vehicle, were delivered subcutaneously by mini pump (9 microgram/24h) starting on day 3 post-stroke.
Results: We found a 1.7-fold increase in the number of GABAergic synapses containing the alpha 1 receptor subunit in layer 5 of the peri-infarct cortex (P<0.01), but not in layer 2/3. There was an associated increase in spontaneous inhibitory post-synaptic currents (sIPSC) specific to layer 5 pyramidal neurons (sIPSC charge (fC): -403±27.8 (control) vs -724±166 (stroke); p=0.03). This effect was transient, occurring during the onset of functional recovery. Enhancing phasic GABA signaling by treating mice with low dose zolpidem, an FDA-approved alpha 1 receptor subunit agonist, increased behavioral recovery without altering infarct size.
Conclusions: These data provide the first evidence that enhanced GABA-mediated synaptic activity during the recovery phase improves stroke outcome, identifying a novel therapeutic strategy for stroke. It also indicates zolpidem as a potential drug to improve recovery.
Patient Care: It identifies potentiation of GABA signaling in the (sub-acute) repair phase as a novel therapeutic strategy for stroke. It suggests that low dose zolpidem, an FDA-approved sleep drug when used at higher doses, could be a pharmacological agent to treat stroke in the repair/recovery phase.
Learning Objectives: By the conclusion of this session participants should: a) understand that phasic GABA signaling is increased at the onset of stroke recovery in a cortical-layer specific manner, b) understand that enhancing phasic GABA signaling in the repair phase enhanced post-stroke recovery, c) consider low dose zolpidem as a potential drug treatment in the repair phase of stroke to improve recovery.