Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles

Abstract

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 Ca2+ release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knock-out of the IP3 receptors that release Ca2+ from stores does not affect neurovascular coupling. We now show that buffering astrocyte Ca2+ inhibits neuronally-evoked capillary dilation, that astrocyte [Ca2+]i is raised not by release from stores but by entry through ATP-gated channels, and that Ca2+ generates arachidonic acid via phospholipase D2 and diacylglycerol kinase rather than phospholipase A2. In contrast, dilation of arterioles depends on NMDA receptor activation and Ca2+-dependent NO generation by interneurons. These results reveal that different signalling cascades regulate cerebral blood flow at the capillary and arteriole levels.

Mechanisms Mediating Functional Hyperemia in the Brain

“…Mishra and others (2016) reported similar results in the cortex. They studied capillary and arteriole dilation in cortical brain slices, where electrical stimulation of neurons resulted in arteriole and capillary dilation.…”

Genetic targeting of astrocytes in the gliovascular unit of the adult brain

“…A particularly well-supported theory proposes a mechanism and timescale in which astrocyte Ca 2+ levels rise prior to hemodynamic responses 1 . Both early and recent studies used Ca 2+ imaging of brain slices demonstrate that rises in astrocyte Ca 2+ levels are linked to astrocyte function in mediating neuronal and vasculature communication [27][28][29] . We next review two technical ways to monitor astrocyte Ca 2+ fluctuations in the context of monitoring astrocyte-mediated blood flow.…”

“…However, while Ca 2+ responses in the astrocyte somata may be depend on ITPR2 signaling it appears that Ca 2+ flux in distal fine processes appears to be at least partially ITPR2-independent, mediated by extracellular influx or release from mitochondrial stores 47,48 . Taken together with studies that suggest astrocyte fine processes are responsible for neurovascular coupling, ITPR2 manipulations may not be appropriate for studying astrocyte-mediated functional hyperemic responses 27 . Many of the same techniques used to manipulate neuronal activity, including opsins and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have recently been used to manipulate the activity of astrocytes.…”

Mechanistic modelling - a BOLD response to the fMRI information loss problem

“…In short, the presence of neurotransmitters in the synaptic cleft generates an action potential in the post-synaptic neuron, which triggers the release of ATP outside of the neuron activates P2X 1 receptors in adjacent astrocytes resulting in Ca 2+ influx into the astrocyte. The inflow of Ca 2+ activates phospholipase D2 (PLD2) which, after some enzymatic steps, leads to an increase in arachidonic acid (AA) [33] [35]. AA is transformed into several vasoactive substances such as prostaglandin E2 (PGE2), epoxyeicosatrienoic acid (EET), and 20-hydroxyeicosatetraenoic acid (20-HETE) that control the blood vessel actions through intracellular parallell processes, thereby changing the blood flow and causing the post-stimulus peak and the post-peak undershoot of the BOLD response.…”