TY - JOUR
T1 - Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles
AU - Mishra, Anusha
AU - Reynolds, James P.
AU - Chen, Yang
AU - Gourine, Alexander V.
AU - Rusakov, Dmitri A.
AU - Attwell, David
N1 - Publisher Copyright:
© 2016 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/nn.4428
DO - 10.1038/nn.4428
M3 - Article
C2 - 27775719
AN - SCOPUS:84992418532
SN - 1097-6256
VL - 19
SP - 1619
EP - 1627
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 12
ER -