Abstract WMP106: Reversal of Tonic Inhibition Contributes to Recovery of Synaptic Function After Transient Focal Cerebral Ischemia

Introduction: Ischemic stroke is the fourth leading cause of death in the United States and is increasingly being recognized as a disease that occurs in people of all ages, not just the elderly. Studies suggest that the immature developing brain may have a greater degree of plasticity compared to the adult, thereby enhancing functional recovery to a greater extent during development. Hypothesis: Pediatric mice exhibit greater recovery from hippocampal synaptic function following experimental stroke than adults. Methods: Extracellular field recordings of CA1 neurons were performed in acute hippocampal slices prepared at, 7 or 30 days after recovery from middle cerebral artery occlusion (MCAO). A behavioral fear conditioning paradigm was done to evaluate contextual memory in both pediatric and adult mice 30 days after MCAO. α5 GABAA receptors and GABA transporter expression was evaluated by western blot analysis. Results: In adult mice following MCAO, hippocampal long-term potentiation (LTP), defined as an increase in synaptic strength, remained impaired for at least 30 days in the ipsilateral and contralateral, non-injured hemisphere. However, in pediatric mice following MCAO, LTP was only impaired in the ipsilateral side 7 days after MCAO and showed full recovery of synaptic function at 30 days. Behavioral data confirmed these data, showing that only adult mice displayed memory deficits 30 days after MCAO. L655,708 (100nM), an inverse agonist selective for α5 GABAA receptors, rescued LTP in acute slices in both pediatric and adult mice at all-time points tested. Western blot analysis failed to identify any changes in α5 GABAA receptors or GABA transporter (GAT1 or GAT3) levels after MCAO. Conclusion: The present study demonstrates that transient focal ischemia causes functional impairment in the hippocampus and that recovery of behavioral and synaptic function is more robust in the young brain. In addition, inhibition of tonic GABA activity rescues synaptic function, indicating that targeting of excessive GABA activity may provide a therapeutic approach to improve cognitive recovery after stroke.