Energy Metabolism In Astrocytes Research Articles

Regulation of astrocyte energy metabolism by neurotransmitters.

Regulation of astrocyte energy metabolism by neurotransmitters.

Neurotransmitters Regulate Energy Metabolism in Astrocytes: Implications for the Metabolic Trafficking between Neural Cells

In recent years a vast array of experimental evidence has indicated the presence of functional receptors for neurotransmitters on nonneuronal cells, in particular astrocytes. The two neurotransmitters vasoactive intestinal peptide (VIP) and noradrenaline (NA) exert profound, receptor-mediated, metabolic actions on astrocytes. Thus both neurotransmitters stimulate glycogenolysis in primary astrocyte cultures, with EC50s of 3 and 20 nM respectively. Astrocytes display basal glucose utilization rates ranging between 3 and 9 nmol/mg prot/min, a value that is remarkably close to glucose utilization of cerebral cortical grey matter as determined by the 2-deoxyglucose autoradiographic technique. NA markedly enhances glucose uptake and phosphorylation by astrocytes, with an EC50 of 1 microM. The metabolic substrate that is released by astrocytes is predominantly lactate and not glucose. Since lactate can support neuronal activity and synaptic function in vitro, the possibility should be considered that glucose uptake by the brain parenchyma occurs predominantly into astrocytes which subsequently release lactate for the use of neurons.

Portal-systemic encephalopathy: a disorder of neuron-astrocytic metabolic trafficking.

Portal-systemic encephalopathy (PSE) is a major neuropsychiatric complication of chronic liver disease. Neuropathologic evaluation of brain tissue from cirrhotic patients who died in hepatic coma reveals astrocytic (rather than neuronal) changes referred to as Alzheimer type II astrocytosis. Evidence to date suggests that Alzheimer type II astrocytosis is the result of ammonia neurotoxicity. Exposure of cultured astrocytes to concentrations of ammonia equivalent to those encountered in brain in experimental PSE results in Alzheimer type II astrocytosis as well as changes in other astrocytic parameters such as glial fibrillary acidic protein and glycogen metabolism. A second characteristic of PSE is the appearance of increased densities of 'peripheral-type' benzodiazepine receptors (PTBRs) in both brain and peripheral tissues. In brain, PTBRs are highly localized on astrocytic outer mitochondrial membranes. Experimental PSE resulting from portacaval anastomosis in the rat results in increased densities of PTBRs in brain and in increased expression of the endogenous PTBR ligand octadecaneuropeptide in nonneuronal elements. It is suggested that the PTBR and its endogenous ligands could mediate the astrocytic response to chronic exposure to ammonia in PSE. Astrocytic changes in PSE are accompanied by disruption of neuron-astrocytic metabolic trafficking. In particular, reuptake of the neurotransmitter glutamate into the perineuronal astrocyte is inhibited in PSE resulting in glutamatergic synaptic dysregulation and potentially compromised astrocytic energy metabolism. Astrocytic metabolism of monoamine neurotransmitters may also be increased as a result of increased activities of monoamine oxidase MAOB.

Astrocyte volume regulation and ATP and phosphocreatine concentrations after exposure to salicylate, ammonium, and fatty acids.

Cellular volume regulation following swelling in hypo-osmotic phosphate-buffered saline (PBS) and ATP and phosphocreatine concentrations of cells incubated in iso-osmotic or hypo-osmotic PBS were measured in primary cultured rat cerebral astrocytes exposed for 30 min to NH4Cl, salicylate, hexanoate, octanoate, and/or dodecanoate. These compounds have been implicated in the pathogenesis of cerebral edema in Reye's Syndrome. NH4Cl (0.10 - 10 mM) had no effect on astrocyte volume regulation or ATP concentration. Salicylate significantly reduced ATP concentrations at 3.0 mM and 10 mM but had no effect on volume regulation. Hexanoate (10 mM and 30 mM) decreased astrocyte ATP content by over 80% while octanoate (10 mM) reduced ATP content by more than 50%. Concentrations of these fatty acids at or below 3.0 mM had no effect on ATP content. Volume regulation was inhibited by 3.0 mM hexanoate and 3.0 mM octanoate but not lower concentrations. Dodecanoate (0.1-3.0 mM) decreased cellular ATP content by 33-51% in iso-osmotic PBS solutions. Phosphocreatine content was reduced by exposure to salicylate or octanoate at concentrations which had no effect on ATP content. These results indicate that astrocyte energy metabolism and volume regulation may be compromised by agents associated with cerebral edema in Reye's Syndrome. Analysis of the dose-dependence of these effects suggests that inhibition of astrocyte energy metabolism is not sufficient to affect volume regulation.

Correlations between energy metabolism, ion transport, and water content in astrocytes.

Energy metabolism, ion transport, and water content are interrelated in mechanisms of homeostasis of the brain intracellular and extracellular environment. The simplest model of cell homeostasis, the pump-leak hypothesis, incorporates basic relationships between these variables. Although this model accurately calculates steady-state cell volumes, ion concentrations, and metabolic rates, it fails to predict dynamic changes in these properties during elevated extracellular potassium, metabolic inhibition, and osmotic swelling. We have investigated relationships between ions, energy metabolism, and water content in cerebral astrocytes cultured from the neonatal rat. These cells swell more in hypoosmotic phosphate-buffered saline (PBS) containing NaCl than in hypoosmotic PBS with all NaCl replaced equiosmotically by sucrose. Unidirectional Na+ influx also is greater in cells suspended in hypoosmotic, compared with isoosmotic PBS. These data suggest that astrocytes possess a cell volume dependent mechanism of Na+ accumulation. The influx of Na+ during swelling may be coupled to metabolism via Na-K ATPase and may contribute to the sustained swelling of astrocytes observed in hypoosmotic swelling of the brain in situ.

Energy metabolism in glutamatergic neurons, GABAergic neurons and astrocytes in primary cultures.

Several aspects of energy metabolism (glucose utilization, lactate production, 14CO2 production from labeled glucose, glutamate or pyruvate, oxygen consumption and contents of ATP and phosphocreatine) were measured in cerebellar granule cells (glutamatergic) in primary cultures and compared with corresponding data for cerebral cortical neurons (mainly GABA-ergic) and astrocytes. Cerebellar granule cells and astrocytes were metabolically more active than cerebral cortical neurons. Glutamate which is utilized as a major metabolic fuel as astrocytes and, to a lesser extent, in cerebral cortical neurons, was virtually not oxidized in cerebellar granule cells.

The regional distribution of glycogen in rat brain fixed by microwave irradiation

Glycogen concentrations were measured by fluorescence enzymatic assay in rat brains fixed by focused microwave irradiation. Regional glycogen concentrations varied 2.5 fold, ranging from 27.1 nmol glucosyl units/mg protein in the striatum to 52.3 nmol/mg protein in the cerebellum and 69.9 nmol/mg protein in the pons-medulla; other regions were intermediate in concentration. Since glycogen is contained primarily within astrocytes, this regional variation may reflect regional differences in astrocyte energy metabolism.

Effect of monensin on deoxyglucose uptake in cultured astrocytes: energy metabolism is coupled to sodium entry

This study was undertaken to measure the effect of maximal stimulation of sodium pump activity on the rate of energy metabolism in mouse cerebral astrocytes. The rate of uptake of 3H-2-deoxyglucose (3H-2-DG) was measured in astrocyte cultures sodium-loaded either by incubation in a K+-deficient solution or by use of the carboxylic sodium ionophore monensin. Sodium-loading by the first method caused 3H-2-DG uptake to increase by 80%, but the effect was brief (about 5 min) compared with the period of uptake measurement (20 min). In contrast, the presence of monensin (20 microM) caused a sustained 3.4-fold increase in the rate of 3H-2-DG uptake. The concentration-response relationship for monensin indicated a Kd of 1.5 microM and a maximum uptake enhancement of approximately fourfold. The monensin-stimulated uptake of 3H-2-DG was totally inhibited by incubation of the cultures in either K+-free or Na+-free solutions, or in the presence of ouabain (0.4 mM), indicating that the enhancement of uptake was the result of Na+ influx and sodium pump activation. These results raise the possibility that astroglia contribute significantly to regional variations in glucose consumption associated with functional activity in the brain. Ultrastructural analysis showed that sodium-loading in K+-free solution caused swelling confined to the trans face of Golgi stacks. However, monensin (5 microM) caused swelling of the entire Golgi stack, with progressively more severe swelling from cis to trans cisternae and formation of cytoplasmic vacuoles.(ABSTRACT TRUNCATED AT 250 WORDS)