Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles

Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies BOLD functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptors (mGluR5) on astrocytes, evoking Ca(2+) release from internal stores, activating phospholipase A(2) and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knock-out of the IP(3) 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 A(2). In contrast, dilation of arterioles depends on NMDA receptor activation and Ca(2+)-dependent NO generation by interneurons. These results reveal that different signalling cascades regulate cerebral blood flow at the capillary and arteriole levels.