Calcium signaling in astrocytes couples changes in brain activity to regional alterations in cerebral blood flow (CBF) by eliciting vasoconstriction or vasodilation of adjacent arterioles1-7. However, the mechanism for how these disparate astrocyte influences provide appropriate changes in cerebral vascular tone within a cellular environment that has dynamic metabolic requirements remains unclear. The regulation of CBF has recently been shown to be tightly coupled to the lactate/pyruvate ratio and thus the NADH/NAD+ ratio in animals8 and humans9,10. We tested the impact of metabolic changes on the regulation of cerebral blood vessel diameter by astrocytes, by manipulating tissue oxygenation which changes dynamically with brain activity11-14. Using two-photon Ca2+ imaging and uncaging as well as intrinsic nicotinamide adenine dinucleotide (NADH) imaging of single cells as a measure of redox state, we show that the ability of astrocytes to induce vasodilations over vasoconstrictions critically relies on the metabolic state of the tissue. When O2 availability is lowered and astrocyte [Ca2+]i is elevated, astrocyte glycolysis and lactate release are maximized. Extracellular lactate contributes to prostaglandin E2 (PGE2) accumulation by hindering its transporter-mediated uptake, subsequently causing vasodilation. These data reveal the role of metabolic substrates in regulating CBF and provide a mechanism for differential astrocyte control over cerebrovascular diameter during different states of brain activation.

The importance of (micro)vascular contributions to cognitive impairment and dementia (VCID) in aging cannot be overemphasized, and the pathogenesis and prevention of age-related cerebromicrovascular pathologies are a subject of intensive research. In particular, aging impairs the increase in cerebral blood flow triggered by neural activation (termed neurovascular coupling or functional hyperemia), a critical mechanism that matches oxygen and nutrient delivery with the increased demands in active brain regions. From epidemiological, clinical and experimental studies the picture emerges of a complex functional impairment of cerebral microvessels and astrocytes, which likely contribute to neurovascular dysfunction and cognitive decline in aging and in age-related neurodegenerative diseases. This overview discusses age-related alterations in neurovascular coupling responses responsible for impaired functional hyperemia. The mechanisms and consequences of astrocyte dysfunction (including potential alteration of astrocytic endfeet calcium signaling, dysregulation of eicosanoid gliotransmitters and astrocyte energetics) and functional impairment of the microvascular endothelium are explored. Age-related mechanisms (cellular oxidative stress, senescence, circulating IGF-1 deficiency) impairing the function of cells of the neurovascular unit are discussed and the evidence for the causal role of neurovascular uncoupling in cognitive decline is critically examined.

Glial cells actively participate in synaptic transmission. They clear molecules from the synaptic cleft, receive signals from neurons and, in turn, release molecules that can modulate signaling between neuronal elements. Whether glial-derived transmitters can contribute to enduring changes in postsynaptic efficacy, however, remains to be established. In rat hypothalamic paraventricular nucleus, we demonstrate an increase in the amplitude of miniature excitatory postsynaptic currents in response to norepinephrine that requires the release of ATP from glial cells. The increase in quantal efficacy, which likely results from an insertion of AMPA receptors, is secondary to the activation of P2X(7) receptors, an increase in postsynaptic calcium and the activation of phosphatidylinositol 3-kinase. The gliotransmitter ATP, therefore, contributes directly to the regulation of postsynaptic efficacy at glutamatergic synapses in the CNS.

SUMMARY Astrocytes are proposed to participate in brain energy metabolism by supplying substrates to neurons from their glycogen stores and from glycolysis. However, the molecules involved in metabolic sensing and the molecular pathways responsible for metabolic coupling between different cell types in the brain are not fully understood. Here we show that a recently cloned bicarbonate (HCO3−) sensor, soluble adenylyl cyclase (sAC), is highly expressed in astrocytes and becomes activated in response to HCO3− entry via the electrogenic NaHCO3 cotransporter (NBC). Activated sAC increases intracellular cAMP levels, causing glycogen breakdown, enhanced glycolysis, and the release of lactate into the extracellular space, which is subsequently taken up by neurons for use as an energy substrate. This process is recruited over a broad physiological range of [K+]ext and also during aglycemic episodes, helping to maintain synaptic function. These data reveal a molecular pathway in astrocytes that is responsible for brain metabolic coupling to neurons.

The control of cerebral vessel diameter is of fundamental importance in maintaining healthy brain function because it is critical to match cerebral blood flow (CBF) to the metabolic demand of active neurons. Recent studies have shown that astrocytes are critical players in the regulation of cerebral blood vessel diameter and that there are several molecular pathways through which astrocytes can elicit these changes. Increased intracellular Ca 21 in astrocytes has demonstrated a dichotomy in vasomotor responses by causing the constriction as well as the dilation of neighboring blood vessels. The production of arachidonic acid (AA) in astrocytes by Ca 21 sensitive phospholipase A 2 (PLA 2 ) has been shown to be common to both constriction and dilation mechanisms. Constriction results from the conversion of AA to 20-hydroxyeicosatetraenoic acid (20-HETE) and dilation from the production of prostaglandin E 2 (PGE2) or epoxyeicosatrienoic acid (EET) and the level of nitric oxide (NO) appears to dictate which of these two pathways is recruited. In addition the activation of Ca 21 activated K 1 channels in astrocyte endfeet and the efflux of K 1 has also been suggested to modify vascular tone by hyperpolarization and relaxation of smooth muscle cells (SMCs). The wide range of putative pathways indicates that more work is needed to clarify the contributions of astrocytes to vascular dynamics under different cellular conditions. Nonetheless it is clear that astrocytes are important albeit complicated regulators of CBF. V V C 2007 Wiley-Liss, Inc.