Role of Astrocytes in Matching Blood Flow to Neuronal Activity
Introduction
Glial cells were originally described by Virchow (1846) as nonneuronal cells constituting the “glue” of the brain. Later studies classified glial cells in the central nervous system (CNS) as astrocytes, oligodendrocytes, and microglia, each of which has different histological characteristics and functions (Ramon y Cayal, 1911). Once thought to be merely supportive elements, maybe due to the fact that they are nonexcitable cells, glial cells have made the big leap toward the “stars of the show” (Hertz and Zielke, 2004). The big part of the change in their status can be attributed to the findings that glia can integrate neuronal inputs and modulate synaptic activity. In addition, astrocytes can also maintain milieu around the active neurons by regulating extracellular K+ concentration, volume, osmolarity, pH, and concentration of neurotransmitters, particularly glutamate and γ‐aminobutyric acid (GABA) at the synaptic cleft.
Astrocytes are in close association with neurons, can enwrap synaptic terminals (Ventura and Harris, 1999), and have foot processes ensheathing the capillaries. Because of their anatomical location, they were thought for a long time to have an intermediary role in matching neuronal activity to cerebral blood flow (CBF) and metabolism. When neurons in specific brain regions are highly activated, blood flow increases in a temporally and spatially coordinated manner. This coupling between neuronal activity and blood flow, termed functional hyperemia, was first described by Mosso (1880) and confirmed by Roy and Scherrington (1890). As a consequence of neuronal activation blood flow increases in the active area within seconds and thus ensures adequate supply of oxygen and glucose.
This tight coupling between neuronal activity, metabolism, and blood flow has provided the basis for functional brain imaging techniques. Positron emission tomography (PET) uses the coupling between synaptic activity and glucose utility, while functional magnetic resonance imaging (fMRI) is based on the fact that the change in neuronal activity produces variations in the level of hemoglobin oxygenation (Seiyama et al., 2004). The cellular mechanisms of neurovascular coupling have recently been defined and continue to be investigated (Harder 1998, Harder 2000, Harder 2002, Metea 2006). Our group has contributed over the last 10 years to the understanding of such cellular and molecular mechanisms (see Section IV.B.5).
Section snippets
Neurovascular Unit
In 1885, Golgi first described the contact of astrocytic foot processes with arterioles and capillaries (Golgi, 1885). By sending specialized processes to both the vasculature and synaptic contacts, astrocytes have a unique anatomical position between neurons and arterioles to couple neuronal activity to blood supply.
Astrocytes are small cells characterized by small somata (<10 μm) and numerous highly branched processes. The astrocytic process is in close contact with both pre‐ and postsynaptic
Ca2+ Signaling in Astrocytes
Neurons form neuronal networks via synapses while astrocytes form syncytium‐like organizations via gap junctions. Gap junctions are hemichannels that allow the passage of small molecules between cytoplasm of adjacent cells. The major constituent of these hemichannels is connexin 43. These hemichannels have low open permeability in physiological states, but some conditions can change permeability such as an increase in extracellular K+ and low extracellular Ca2+ (Giaume and McCarthy, 1996).
Role of Astrocytic Ca2+ Elevations in Coupling Neuronal Activity to the Vasculature
Because of the anatomical position and the vicinity of foot processes to contractile elements in blood vessels, astrocytes have long been thought to marginally contribute to the regulation of CBF. Studies over the past few years show that synaptic activity, and not the energy deficit due to glucose or oxygen use, is the trigger for neuronal activity‐dependent vasodilation (Sandor, 1999).
Significant evidence supporting a role of astrocytes in regulation of CBF comes from the brain slice
Summary
Astrocytes are no longer regarded as just supportive structures among the brain cells, but play multiple roles in neuronal energy metabolism, synaptic function, pH, water homeostasis, and production of antioxidants in the brain. Despite a growing number of studies confirming the role of astrocytes in neurovascular coupling, the mechanism is still not fully understood. It is now clear that neuronal activity induced Ca2+ elevations and Ca2+ waves are spreading between neighboring astrocytes
References (150)
- et al.
Tripartite synapses: Glia, the unacknowledged partner
Trends Neurosci.
(1999) - et al.
Atypical neural messengers
Trends Neurosci.
(2001) Neuron‐astrocyte interactions: Partnership for normal function and disease in the central nervous system
Mayo Clin. Proc.
(2005)- et al.
Neuron‐astrocyte cross‐talk during synaptic transmission: Physiological and neuropathological implications
Prog. Brain Res.
(2001) - et al.
Regulation of endothelium‐derived vasoactive autacoid production by hemodynamic forces
Trends Pharmacol. Sci.
(2003) - et al.
Epoxyeicosatrienoic acids and their sulfonimide derivatives stimulate tyrosine phosphorylation and induce mitogenesis in renal epithelial cells
J. Biol. Chem.
(1998) - et al.
Transfection of an active cytochrome P450 arachidonic acid epoxygenase indicates that 14,15‐epoxyeicosatrienoic acid functions as an intracellular second messenger in response to epidermal growth factor
J. Biol. Chem.
(1999) - et al.
Effect of neuronal NO synthase inhibition on the cerebral vasodilatory response to somatosensory stimulation
Brain Res.
(1996) - et al.
Conducted vascular responses: Communication across the capillary bed
Microvasc. Res.
(1998) - et al.
Neuronal activity triggers calcium waves in hippocampal astrocyte networks
Neuron
(1992)
Astroglial processes around identified glutamatergic synapses contain glutamine synthetase: Evidence for transmitter degradation
Brain Res.
Metabolism and functions of glutathione in brain
Prog. Neurobiol.
Control of gap‐junctional communication in astrocytic networks
Trends Neurosci.
Astrocytic control of glutamatergic activity: Astrocytes as stars of the show
Trends Neurosci.
Cyclooxygenase‐derived metabolites of 8,9‐epoxyeicosatrienoic acid are potent mitogens for cultured rat glomerular mesangial cells
Biochem. Biophys. Res. Commun.
Nitric oxide and adenosine mediate vasodilation during functional activation in cerebellar cortex
Neuropharmacology
Neurovascular relationships in hippocampal slices: Physiological and anatomical studies of mechanisms underlying flow‐metabolism coupling in intraparenchymal microvessels
Neuroscience
Calcium signaling in retinal glial cells and its effect on neuronal activity
Prog. Brain Res.
Role of nitric oxide and cyclic GMP as mediators of endothelium‐independent neurogenic relaxation in bovine mesenteric artery
Circ. Res.
Inhibition of brain P‐450 arachidonic acid epoxygenase decreases baseline cerebral blood flow
Am. J. Physiol.
Molecular characterization of an arachidonic acid epoxygenase in rat brain astrocytes
Stroke
Role of P‐450 arachidonic acid epoxygenase in the response of cerebral blood flow to glutamate in rats
Stroke
Brain synthesis and cerebrovascular action of epoxygenase metabolites of arachidonic acid
J. Neurochem.
Metabolism of arachidonic acid to epoxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, and prostaglandins in cultured rat hippocampal astrocytes
J. Neurochem.
Endothelial influences on cerebrovascular tone
J. Appl. Physiol.
Glutamate‐dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons
Eur. J. Neurosci.
Calcium elevation in astrocytes causes an NMDA receptor‐dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons
J. Neurosci.
Astrocyte‐induced modulation of synaptic transmission
Can. J. Physiol. Pharmacol.
SNARE protein‐dependent glutamate release from astrocytes
J. Neurosci.
Dynamic signaling between astrocytes and neurons
Annu. Rev. Physiol.
Contributions of endothelial and neuronal nitric oxide synthases to cerebrovascular responses to hyperoxia
J. Cereb. Blood Flow Metab.
L‐NA‐sensitive rCBF augmentation during vibrissal stimulation in type III nitric oxide synthase mutant mice
J. Cereb. Blood Flow Metab.
The cyclooxygenase inhibitors indomethacin and Rofecoxib reduce regional cerebral blood flow evoked by somatosensory stimulation in rats
Exp. Biol. Med. (Maywood)
Astrocytes generate Na+‐mediated metabolic waves
Proc. Natl. Acad. Sci. USA
Prostaglandins stimulate calcium‐dependent glutamate release in astrocytes
Nature
P‐450 epoxygenase and NO synthase inhibitors reduce cerebral blood flow response to N‐methyl‐d‐aspartate
Am. J. Physiol. Heart Circ. Physiol.
Mechanisms of endotoxin‐induced dilatation of cerebral arterioles
Am. J. Physiol.
Teaching resources. Glial intercellular waves
Sci. STKE
Local uncoupling of the cerebrovascular and metabolic responses to somatosensory stimulation after neuronal nitric oxide synthase inhibition
J. Cereb. Blood Flow Metab.
Metabolism of a long‐chain diacylglycerol by permeabilized A10 smooth muscle cells
Am. J. Physiol.
Primary and secondary Ca2+ concentration changes resulting from transmitter stimulation in dendrites of neurons from the mammalian hippocampus
Ann. NY Acad. Sci.
Glutamate induces calcium waves in cultured astrocytes: Long‐range glial signaling
Science
Astrocytic gap junctions remain open during ischemic conditions
J. Neurosci.
Connexins regulate calcium signaling by controlling ATP release
Proc. Natl. Acad. Sci. USA
ATP‐mediated glia signaling
J. Neurosci.
Localized dynamic changes in cortical blood flow with whisker stimulation corresponds to matched vascular and neuronal architecture of rat barrels
J. Cereb. Blood Flow Metab.
Regulation of the ecto‐nucleotidase pathway in rat hippocampal nerve terminals
Neurochem. Res.
Coupling of cerebral blood flow to neuronal activation: Role of adenosine and nitric oxide
Am. J. Physiol.
Dilation of cerebral arterioles by cytochrome P‐450 metabolites of arachidonic acid
Am. J. Physiol.
Activation of protein kinase C blocks astroglial gap junction communication and inhibits the spread of calcium waves
J. Neurochem.
Cited by (66)
Central nervous system physiology: Cerebrovascular
2018, Pharmacology and Physiology for Anesthesia: Foundations and Clinical ApplicationRole of astrocytes in memory and psychiatric disorders
2014, Journal of Physiology ParisCitation Excerpt :Astrocytes are known to help neurons recycle glutamate and GABA. Glutamate is uptaken and transformed to glutamine, which is then released and used by the presynaptic neuron (for a review see Jakovcevic and Harder, 2007; Charles, 2005). Glutamate uptake is sodium-dependent, which leads to sodium influx, which in turn triggers an increase in astrocytic glucose uptake and its conversion into lactate via activation of the sodium–potassium ATPase.
Effect of non-steroid anti-inflammatory drugs on neurovascular coupling in humans
2014, Journal of the Neurological SciencesAstrocyte-neuron interactions: From experimental research-based models to translational medicine
2014, Progress in Molecular Biology and Translational Science