Assembly of a perivascular astrocyte protein scaffold at the mammalian blood–brain barrier is dependent on α-syntrophin

Abstract

α‐Syntrophin, a member of the dystrophin‐associated protein complex, is required for proper localization of the water channel aquaporin‐4 at the blood–brain barrier. Mice lacking α‐syntrophin have reduced levels of aquaporin‐4 in perivascular astroglial endfeet. Consequently, they exhibit reduced edema and infarct volume in brain trauma models and reduced K+ clearance from the neuropil, leading to increased seizure susceptibility. We have used the α‐syntrophin null mice to investigate whether α‐syntrophin is required for proper localization of other components of the dystrophin complex at the blood–brain barrier. We find that α‐syntrophin is required for the full recruitment of γ2‐syntrophin and α‐dystrobrevin‐2 to glial endfeet in adult cerebellum. In contrast, the localization of β1‐ and β2‐syntrophin and α‐dystrobrevin‐1 at the blood–brain barrier is not dependent on the presence of α‐syntrophin. The localization patterns of α‐dystrobrevin‐1 and ‐2 in wild type cerebellum are strikingly different; while α‐dystrobrevin‐1 is present in glial endfeet throughout the cerebellum, α‐dystrobrevin‐2 is restricted to glial endfeet in the granular layer alone. Finally, we show that the enrichment of dystrophin in glial endfeet depends on the presence of α‐syntrophin. This finding is the first demonstration that dystrophin localization is dependent on syntrophin. Since the localization of γ2‐syntrophin, α‐dystrobrevin‐2, and dystrophin is contingent on α‐syntrophin, we conclude that α‐syntrophin is a central organizer of the astrocyte dystrophin complex, an important molecular scaffold for localization of aquaporin‐4 at the blood–brain barrier.