Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles

Anusha Mishra, James P. Reynolds, Yang Chen, Alexander V. Gourine, Dmitri A. Rusakov, David Attwell

Research output: Contribution to journalArticle

154 Scopus citations

Abstract

Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies blood oxygen level-dependent functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptor 5 (mGluR5) on astrocytes, evoking Ca 2+ release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knockout of the inositol 1,4,5-trisphosphate receptors that release Ca 2+ from stores does not affect neurovascular coupling. We now show that buffering astrocyte Ca 2+ inhibits neuronally evoked capillary dilation, that astrocyte [Ca 2+ ] i is raised not by release from stores but by entry through ATP-gated channels, and that Ca 2+ generates arachidonic acid via phospholipase D2 and diacylglycerol kinase rather than phospholipase A2. In contrast, dilation of arterioles depends on NMDA receptor activation and Ca 2+ -dependent NO generation by interneurons. These results reveal that different signaling cascades regulate cerebral blood flow at the capillary and arteriole levels.

Original languageEnglish (US)
Pages (from-to)1619-1627
Number of pages9
JournalNature Neuroscience
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2016

ASJC Scopus subject areas

  • Neuroscience(all)

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    Mishra, A., Reynolds, J. P., Chen, Y., Gourine, A. V., Rusakov, D. A., & Attwell, D. (2016). Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nature Neuroscience, 19(12), 1619-1627. https://doi.org/10.1038/nn.4428