Abstract TP97: Improved Long-Term Outcome after Transient Cerebral Ischemia in Aquaporin-4 Knockout Mice
Introduction: Aquaporin-4 (AQP4) is an abundant aquaporin in brain that has been hypothesized to play a central role in edema formation. Furthermore, AQP4 downregulation has been correlated with connexin 43 (Cx43) downregulation, a gap junction protein important for ion and water transport through astrocyte networks. AQP4 deletion in mice was shown to be beneficial at 24 hours after permanent occlusion of the middle cerebral artery (MCAO). However, the long-term consequences of AQP4 deletion on behavior, edema, and tissue properties after stroke have not been studied.
Objective: Following transient MCAO, behavior, lesion volumes, blood brain barrier (BBB) integrity, neuroinflammation, and astrocyte network properties with Cx43 expressions were assessed for 14 days in wild type (WT) and AQP4-/- mice.
Methods: Transient (30-min) filament MCAO was performed on AQP4-/- (n=5) and WT (n=8) mice on a CD1 genetic background. Behavioral outcomes were assessed by rotarod, beam balance, and foot fault tests from 1 to 14 days (d) post injury. Temporal magnetic resonance imaging (MRI) was undertaken to assess lesion volume. Mice were transcardially perfused at 15 d and the brains were extracted and frozen to perform immunohistochemical analysis for IgG, AQP4, Cx43, and glial fibrillary acidic protein (GFAP).
Results: MRI showed significantly smaller lesion volume in AQP4-/- at 1, 3, 7, and 14d. AQP4-/- mice also had improved motor function recovery with 54% and 75% decreased number of foot-faults than WT mice respectively at 1 and 3 d; and 60% increased time spent on the rotarod compared to WT over the 14 days after stroke onset. AQP4-/- mice had reduced IgG extravasation and Cx43 expression but increased GFAP staining compared to WT at 14d, suggesting, respectively, less BBB disruption and modified astrocyte network properties combined with altered neuroinflammation fates.
Conclusion: AQP4 deletion resulted in improved long-term functional recovery associated with decreased lesion volumes and improved BBB integrity. Although more work must be done, the beneficial outcomes in AQP4-/- may partly be due to decreased Cx43 as well, resulting in not only decreased edema formation through AQP4, but also in decreased spread of edema through the astrocyte network.
- © 2012 by American Heart Association, Inc.