TRPV4 channels contribute to calcium transients in astrocytes and neurons during peri-infarct depolarizations in a stroke model

Glia. 2017 Sep;65(9):1550-1561. doi: 10.1002/glia.23183. Epub 2017 Jun 22.

Abstract

Stroke is one of the leading causes of death and long-term disability. In the penumbra, that is, the area surrounding the infarct core, peri-infarct depolarizations (PIDs) are accompanied by strong intracellular calcium elevations in astrocytes and neurons, thereby negatively affecting infarct size and clinical outcome. The dynamics of PIDs and the cellular pathways that are involved during PID formation and progression remain incompletely understood. We have previously shown that inositol triphosphate-gated calcium release from internal stores is a major component of PID-related astroglial calcium signals, but whether external calcium influx through membrane-localized channels also contributes to PIDs has remained unclear. In this study, we investigated the role of two astroglial membrane channels, transient receptor vanilloid 4 (TRPV4) channel and aquaporin-4 (AQP4). We combined in vivo multiphoton microscopy, electrophysiology as well as laser speckle contrast imaging with the middle cerebral artery occlusion stroke model. Using knockout mice and pharmacological inhibitors, we found that TRPV4 channels contribute to calcium influx into astrocytes and neurons and subsequent extracellular glutamate accumulation during PIDs. AQP4 neither influenced PID-related calcium signals nor PID-related edema of astrocyte somata. Both channels did not alter the dynamics, frequency and cerebrovascular response of PIDs in the penumbra. These data indicate that TRPV4 channels may represent a potential target to ameliorate the PID-induced calcium overload of astrocytes and neurons during acute stroke.

Keywords: Ischemia; astroglia; iGluSnFR; in vivo imaging; spreading depolarization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 4 / genetics
  • Aquaporin 4 / metabolism
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Brain / blood supply
  • Brain / metabolism
  • Brain / pathology
  • Brain Edema / metabolism
  • Brain Edema / pathology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Calcium / metabolism*
  • Cerebrovascular Circulation / physiology
  • Connexin 43 / genetics
  • Connexin 43 / metabolism
  • Disease Models, Animal
  • Female
  • Glutamic Acid / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism*
  • Neurons / pathology
  • Stroke / metabolism*
  • Stroke / pathology
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*

Substances

  • Aqp4 protein, mouse
  • Aquaporin 4
  • Connexin 43
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Glutamic Acid
  • Calcium