Microglia-astrocyte interaction underlies aquaporin-4 dysregulation in the mouse cortex

Brain water homeostasis relies on the coordinated actions of glial cells. In particular, astrocytes play an essential role in facilitating perivascular water exchange between cerebrospinal fluid and interstitial fluid through aquaporin-4 (AQP4), a water channel highly concentrated at astrocytic endfeet. Dysregulation of AQP4 localization is implicated in various neuropathologies, but its underlying mechanisms are unclear. Although astrocytes and microglia both express {beta}-adrenergic receptors ({beta}-AdRs), whether {beta}-AdR signaling modulates astrocytic AQP4 polarization through microglial activation has not yet been investigated. Here, we hypothesized that microglial activation mediates the {beta}-AdR-induced loss of astrocytic AQP4 polarization. To test this hypothesis, we topically applied the {beta}-AdR agonist, isoproterenol, to the primary visual cortex of anesthetized mice and evaluated AQP4 polarization using double immunohistochemistry. Acute {beta}-AdR activation (3 h) significantly reduced perivascular AQP4 polarization and enhanced local microglial reactivity. Both pharmacological inhibition of microglial activity with minocycline and microglial depletion via dietary administration of the CSF1R antagonist, PLX5622, prevented AQP4 dysregulation induced by isoproterenol. These findings demonstrate that microglial activation is required for {beta}-AdR agonist-induced AQP4 dysregulation in the mouse cortex, revealing a previously unrecognized microglia-astrocyte interaction linking adrenergic signaling to glial water homeostasis.