Oligodendroglia: metabolic supporters of neurons
01 Sep 2017-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 127, Iss: 9, pp 3271-3280
TL;DR: This Review will discuss the current understanding of this metabolic supportive function of oligodendrocytes and its potential impact in human neurodegenerative disease and related animal models.
Abstract: Oligodendrocytes are glial cells that populate the entire CNS after they have differentiated from oligodendrocyte progenitor cells. From birth onward, oligodendrocytes initiate wrapping of neuronal axons with a multilamellar lipid structure called myelin. Apart from their well-established function in action potential propagation, more recent data indicate that oligodendrocytes are essential for providing metabolic support to neurons. Oligodendrocytes transfer energy metabolites to neurons through cytoplasmic "myelinic" channels and monocarboxylate transporters, which allow for the fast delivery of short-carbon-chain energy metabolites like pyruvate and lactate to neurons. These substrates are metabolized and contribute to ATP synthesis in neurons. This Review will discuss our current understanding of this metabolic supportive function of oligodendrocytes and its potential impact in human neurodegenerative disease and related animal models.
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171 citations
Cites background from "Oligodendroglia: metabolic supporte..."
...In contrast, oligodendrocytes are well connected to the axon and perfectly positioned to support the metabolic demands of neurons [151]....
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...Energy buffering and transport Creatine Improved lifespan, motor neuron survival, and motor function in mutant SOD1G93A mice [87] No efficacy in phase II/III clinical trials [55, 139, 151]...
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University of Buenos Aires1, Boston Children's Hospital2, Northwestern University3, University Kebangsaan Malaysia Medical Centre4, University of Copenhagen5, Moscow State University6, National Academy of Sciences of Belarus7, University of Bremen8, University of California, San Diego9, Federal University of Rio de Janeiro10, Queen's University11, Birla Institute of Technology and Science12, Indian Institute of Toxicology Research13, Baylor College of Medicine14, University of Western Australia15, Harry Perkins Institute of Medical Research16, Tata Institute of Fundamental Research17, Government of India18, Royal Children's Hospital19, Leibniz Institute for Neurobiology20, Jikei University School of Medicine21, Indian Institute of Chemical Biology22, Nencki Institute of Experimental Biology23, University of Minho24, Indira Gandhi National Tribal University25, University of Queensland26, Technische Universität München27, Otto-von-Guericke University Magdeburg28, Tokyo University of Pharmacy and Life Sciences29
TL;DR: This review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity.
Abstract: The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia-neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic ('housekeeping') cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non-neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS.
133 citations
References
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TL;DR: It is reported that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes and is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.
Abstract: Glutamate, released at a majority of excitatory synapses in the central nervous system, depolarizes neurons by acting at specific receptors. Its action is terminated by removal from the synaptic cleft mostly via Na(+)-dependent uptake systems located on both neurons and astrocytes. Here we report that glutamate, in addition to its receptor-mediated actions on neuronal excitability, stimulates glycolysis--i.e., glucose utilization and lactate production--in astrocytes. This metabolic action is mediated by activation of a Na(+)-dependent uptake system and not by interaction with receptors. The mechanism involves the Na+/K(+)-ATPase, which is activated by an increase in the intracellular concentration of Na+ cotransported with glutamate by the electrogenic uptake system. Thus, when glutamate is released from active synapses and taken up by astrocytes, the newly identified signaling pathway described here would provide a simple and direct mechanism to tightly couple neuronal activity to glucose utilization. In addition, glutamate-stimulated glycolysis is consistent with data obtained from functional brain imaging studies indicating local nonoxidative glucose utilization during physiological activation.
2,521 citations
"Oligodendroglia: metabolic supporte..." refers background in this paper
...Long-term memory formation in the hippocampus of these rats was severely impaired upon hippocampal-specific inhibition of either MCT1, MCT2, or MCT4 expression; MCT1 or MCT4 deficiency could be rescued with injection of l-lactate but not equicaloric glucose....
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...MCT1–MCT4 cotransport monocarboxylates like lactate, pyruvate, and ketone bodies with H+ ions across plasma membranes according to their concentration gradient....
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...Early publications suggested that astrocytes play the foremost role in providing neurons with lactate through MCT1 and MCT4 (32, 52); however, it is now well established that MCT1 is strongly expressed by oligodendrocytes at the abaxonal and adaxonal myelinic channels and that oligodendrocyte MCT1 mediates metabolic support to neurons (43, 53)....
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...MCT4 (which has the lowest affinity for lactate) is expressed in astrocytes (50)....
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...Rafiki A, Boulland JL, Halestrap AP, Ottersen OP, Bergersen L. Highly differential expression of the monocarboxylate transporters MCT2 and MCT4 in the developing rat brain....
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TL;DR: The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset, according to a prospective, double-blind, placebo-controlled trial in 155 outpatients with Amyotrophicateral sclerosis.
Abstract: Background Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis. Methods To evaluate the efficacy and safety of the antiglutamate agent riluzole, we conducted a prospective, double-blind, placebo-controlled trial in 155 outpatients with amyotrophic lateral sclerosis. The dose of riluzole was 100 mg per day. Randomization was stratified according to the site of disease onset (the bulbar region or the limbs). The primary end points were survival and rates of change in functional status. The main secondary end point was change in muscle strength. Analyses were undertaken after 12 months of treatment and at the end of the placebo-controlled period (median follow-up, 573 days). Results After 12 months, 45 of 78 patients (58 percent) in the placebo group were still alive, as compared with 57 of 77 patients (74 percent) in the riluzole group...
1,982 citations
"Oligodendroglia: metabolic supporte..." refers background in this paper
...No cure or treatment is currently available, although two drugs (riluzole and edaravone) increase survival and slightly slow disease (105, 106)....
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TL;DR: The current understanding of multiple sclerosis immunopathology is discussed, long-standing hypotheses regarding the role of the immune system in the disease are evaluated, and key questions that are still unanswered are delineated.
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1,324 citations
"Oligodendroglia: metabolic supporte..." refers background in this paper
...Adaptive changes in myelin in human brain have also been suggested by several studies (26, 27)....
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