Deletion of Aquaporin-4 Curtails Extracellular Glutamate Elevation in Cortical Spreading Depression in Awake Mice

Cereb Cortex. 2017 Jan 1;27(1):24-33. doi: 10.1093/cercor/bhw359.


Cortical spreading depression (CSD) is a phenomenon that challenges the homeostatic mechanisms on which normal brain function so critically depends. Analyzing the sequence of events in CSD holds the potential of providing new insight in the physiological processes underlying normal brain function as well as the pathophysiology of neurological conditions characterized by ionic dyshomeostasis. Here, we have studied the sequential progression of CSD in awake wild-type mice and in mice lacking aquaporin-4 (AQP4) or inositol 1,4,5-triphosphate type 2 receptor (IP3R2). By the use of a novel combination of genetically encoded sensors that a novel combination - an unprecedented temporal and spatial resolution, we show that CSD leads to brisk Ca2+ signals in astrocytes and that the duration of these Ca2+ signals is shortened in the absence of AQP4 but not in the absence of IP3R2. The decrease of the astrocytic, AQP4-dependent Ca2+ signals, coincides in time and space with a decrease in the duration of extracellular glutamate overflow but not with the initial peak of the glutamate release suggesting that in CSD, extracellular glutamate accumulation is extended through AQP4-dependent glutamate release from astrocytes. The present data point to a salient glial contribution to CSD and identify AQP4 as a new target for therapy.

Keywords: AQP4; IP3R2; astrocyte; calcium; glia; homeostasis; migraine.

MeSH terms

  • Animals
  • Aquaporin 4 / genetics
  • Aquaporin 4 / metabolism*
  • Astrocytes / physiology*
  • Calcium Signaling / physiology
  • Cortical Spreading Depression / physiology*
  • Down-Regulation
  • Extracellular Fluid / metabolism*
  • Glutamic Acid / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Wakefulness / physiology*


  • Aqp4 protein, mouse
  • Aquaporin 4
  • Glutamic Acid