Stimulation-Induced Increases of Astrocytic Oxidative Metabolism in Rats and Humans Investigated with 1-<sup>11</sup>C-Acetate

Brain metabolism is characterized by fuel monodependence, high-energy expenditure, autonomy from the rest of body, local recycling, and marked division of labor between cell types. Although neurons spend most of the brain's energy on signaling, astrocytes bear the brunt of the metabolic load, controlling the composition of the interstitial fluid, supplying neurons with energy substrates and precursors for biosynthesis, and recycling neurotransmitters, oxidized scavengers, and other waste products. Outstanding questions in this field are the role of oligodendrocytes, the metabolic behavior of the different subtypes of astrocytes during development and disease, and the emerging notion that metabolism may participate directly in information processing. T he energy requirements of the central nervous system (CNS) are very high compared with those of other organs. Although the brain accounts for merely 2% of body weight, it receives 15% of cardiac output, and uses 20% of the oxygen and 25% of the glucose of the total body turnover (Magistretti 2008). A special microarchitecture has evolved to support this extreme need, in which glial cells play a central role (Fig. 1). The microvasculature consists of a complex and dense network of highly interconnected blood vessels (Weber et al. 2008;Blinder et al. 2013) to ensure adequate delivery of oxygen and glucose. Although oxygen diffuses freely into the parenchyma, glucose and other hydrophilic energy substrates are translocated across membranes via specific transporter proteins (Fig. 1). The astrocyte is a polarized cell. One set of astrocytic processes ensheaths the vasculature and a second set reaches toward the synapse, the site of highest energy demand (Harris et al. 2012). Much of the ATP produced in the brain is spent by neurons on the recovery of ion gradients challenged by postsynaptic potentials, with a smaller investment in action potentials and neurotransmitter recycling (Harris et al. 2012). Astrocytes consume considerable energy for their own needs and the cycling of metabolically relevant substances for neurons. These metabolic processes in astrocytes and neurons are the basis for brain mapping using functional magnetic resonance imaging and positron emission tomography (PET)-methods that capture local metabolism either directly or indirectly via hemodynamic changes (Magistretti 2008;Belanger et al. 2011a). Levels of energy consumption in the whole brain are almost constant. However, individual neurons can increase their consumption dramatically. For example, a striatal neuron may Overview of astrocytic metabolism. (Inset) Astrocytes (green) reside between blood vessels (red) and neurons (yellow). Neurons and oligodendrocytes (blue) are not in direct contact with vessels. Astrocytes form metabolic domains and are coupled by gap junctions, through which they exchange metabolites and ions. Energy: The main energy substrate of the brain is glucose (glc), which crosses the endothelium and enters astrocytes via the glucose transporter GLUT1. Glucose is converted b...

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“…11 C]-acetate in rat and human (Wyss et al 2009). Acetate can also be labeled with the stable isotope […”

Section: Measuring Metabolism Toward Single-cell Readoutsmentioning

confidence: 96%

The Astrocyte: Powerhouse and Recycling Center

Weber

Barros

2015

Cold Spring Harb Perspect Biol

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“…For the measurement of the time-course of 1-11 C-D-lactate in the brain, an intracortical beta probe was used. 16,17 Twenty minutes of data were acquired at baseline condition after injection of 200 to 300 MBq of radiotracer in 5 animals. In one of these animals, baseline cerebral blood flow was determined before 1-11 C-D-lactate acquisition using 15 O-H 2 O and the methodology described previously.…”

Section: Experiments Using 11 C-d-lactate In Sprague Dawley Ratsmentioning

confidence: 99%

A Probable Dual Mode of Action for Both L- and D-Lactate Neuroprotection in Cerebral Ischemia

Castillo

Rosafio

Wyss

et al. 2015

J Cereb Blood Flow Metab

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Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

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“…However, the contribution of mitochondria to the metabolic response remains elusive , although direct and indirect evidence suggests a certain degree of oxidative activity in astrocytes (Lovatt et al, 2007;Wyss et al, 2009) and astrocytes also experience activity-dependent increases in cytosolic Ca 2ϩ (Schummers et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Glutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes

Azarias¹,

Perreten²,

Lengacher³

et al. 2011

J. Neurosci.

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During synaptic activity, the clearance of neuronally released glutamate leads to an intracellular sodium concentration increase in astrocytes that is associated with significant metabolic cost. The proximity of mitochondria at glutamate uptake sites in astrocytes raises the question of the ability of mitochondria to respond to these energy demands. We used dynamic fluorescence imaging to investigate the impact of glutamatergic transmission on mitochondria in intact astrocytes. Neuronal release of glutamate induced an intracellular acidification in astrocytes, via glutamate transporters, that spread over the mitochondrial matrix. The glutamate-induced mitochondrial matrix acidification exceeded cytosolic acidification and abrogated cytosol-to-mitochondrial matrix pH gradient. By decoupling glutamate uptake from cellular acidification, we found that glutamate induced a pH-mediated decrease in mitochondrial metabolism that surpasses the Ca 2ϩ -mediated stimulatory effects. These findings suggest a model in which excitatory neurotransmission dynamically regulates astrocyte energy metabolism by limiting the contribution of mitochondria to the metabolic response, thereby increasing the local oxygen availability and preventing excessive mitochondrial reactive oxygen species production.

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Stimulation-Induced Increases of Astrocytic Oxidative Metabolism in Rats and Humans Investigated with 1-¹¹C-Acetate

Cited by 42 publications

References 40 publications

The Astrocyte: Powerhouse and Recycling Center

The Astrocyte: Powerhouse and Recycling Center

A Probable Dual Mode of Action for Both L- and D-Lactate Neuroprotection in Cerebral Ischemia

Glutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes

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Stimulation-Induced Increases of Astrocytic Oxidative Metabolism in Rats and Humans Investigated with 1-11C-Acetate

Cited by 42 publications

References 40 publications

The Astrocyte: Powerhouse and Recycling Center

The Astrocyte: Powerhouse and Recycling Center

A Probable Dual Mode of Action for Both L- and D-Lactate Neuroprotection in Cerebral Ischemia

Glutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes

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Stimulation-Induced Increases of Astrocytic Oxidative Metabolism in Rats and Humans Investigated with 1-¹¹C-Acetate