Neuron-Astrocyte Interactions: Partnership for Normal Function and Disease in the Central Nervous System
2005; Elsevier BV; Volume: 80; Issue: 10 Linguagem: Inglês
10.4065/80.10.1326
ISSN1942-5546
Autores Tópico(s)Neurogenesis and neuroplasticity mechanisms
ResumoInteractions between neurons and astrocytes are critical for signaling, energy metabolism, extracellular ion homeostasis, volume regulation, and neuroprotection in the central nervous system. Astrocytes face the synapses, send end-foot processes that enwrap the brain capillaries, and form an extensive network interconnected by gap junctions. Astrocytes express several membrane proteins and enzymes that are critical for uptake of glutamate at the synapses, ammonia detoxification, buffering of extracellular K+, and volume regulation. They also participate in detection, propagation, and modulation of excitatory synaptic signals, provide metabolic support to the active neurons, and contribute to functional hyperemia in the active brain tissue. Disturbances of these neuron-astrocyte interactions are likely to play an important role in neurologic disorders including cerebral ischemia, neurodegeneration, migraine, cerebral edema, and hepatic encephalopathy. Interactions between neurons and astrocytes are critical for signaling, energy metabolism, extracellular ion homeostasis, volume regulation, and neuroprotection in the central nervous system. Astrocytes face the synapses, send end-foot processes that enwrap the brain capillaries, and form an extensive network interconnected by gap junctions. Astrocytes express several membrane proteins and enzymes that are critical for uptake of glutamate at the synapses, ammonia detoxification, buffering of extracellular K+, and volume regulation. They also participate in detection, propagation, and modulation of excitatory synaptic signals, provide metabolic support to the active neurons, and contribute to functional hyperemia in the active brain tissue. Disturbances of these neuron-astrocyte interactions are likely to play an important role in neurologic disorders including cerebral ischemia, neurodegeneration, migraine, cerebral edema, and hepatic encephalopathy. The normal function of the central nervous system depends on adequate maintenance of the neuronal microenvironment. This requires regulation of the extracellular ionic composition, osmolarity, and pH, and prevention of accumulation of neurotransmitters at the synaptic space. There also should be a continuous supply of fuel for oxidative neuronal metabolism and local increase in blood flow to meet the demands of the active neuronal populations. Increasing evidence shows that the astrocytes have a critical role in all these processes. Neurons and astrocytes are intimately intermingled and form 2 separate but highly interactive networks: a neuronal network connected via synapses and an astrocyte network forming a syncytium interconnected via gap junctions. Bidirectional neuron-astrocyte interactions are critical for the normal function and survival of the central nervous system. Many of these interactions have been demonstrated in vitro in astrocytes obtained from selected brain regions. Therefore, whether these interactions occur in vivo in widespread areas of the human central nervous system is still undetermined. If this occurs, neuron-astrocyte interactions may be critical to understanding the mechanisms of neurologic disease. This review focuses on selected aspects of these interactions and their potential clinical implications. Astrocytes typically extend processes that define a 3-dimensional space. At least in some brain regions, the distribution of astrocytes is highly organized so that there is a parcellation of the neuropil into small astrocyte-defined domains.1Nedergaard M Ransom B Goldman SA New roles for astrocytes: redefining the functional architecture of the brain.Trends Neurosci. 2003; 26: 523-530Abstract Full Text Full Text PDF PubMed Scopus (989) Google Scholar The cerebral microvessels typically are positioned along the interfaces between linearly arranged adjacent astrocytic domains resembling the organization seen in endocrine tissues.2Kacem K Lacombe P Seylaz J Bonvento G Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study.Glia. 1998; 23: 1-10Crossref PubMed Scopus (278) Google Scholar Whether this pattern of organization occurs in all areas of the central nervous system is still undetermined because astrocytes are likely to form functionally heterogeneous populations. The astrocytes are polarized into 2 functional domains: the largest portion of the astrocyte membrane faces the synapses, and the remainder abut the capillaries, forming the astrocytic end-foot processes (Figure 1).2Kacem K Lacombe P Seylaz J Bonvento G Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study.Glia. 1998; 23: 1-10Crossref PubMed Scopus (278) Google Scholar All the synapses lying within a given volumetrically defined compartment can be influenced by a single astrocyte. At this level, the astrocyte has a key role in maintaining the milieu around the active neurons by regulating extracellular K+ ([K+]o) concentration, volume, osmolarity, and pH, as well as the concentration of neurotransmitters, particularly the excitatory neurotransmitter L-glutamate and the inhibitory neurotransmitter γ-aminobutyric acid (GABA), at the synaptic space. To fulfill these functions, the astrocytic membrane facing the synapses expresses several ion channel pumps, transporters, and receptors.3Olson JE Li GZ Wang L Lu L Volume-regulated anion conductance in cultured rat cerebral astrocytes requires calmodulin activity.Glia. 2004; 46: 391-401Crossref PubMed Scopus (13) Google Scholar, 4MacAulay N Hamann S Zeuthen T Water transport in the brain: role of cotransporters.Neuroscience. 2004; 129: 1031-1044Crossref PubMed Scopus (93) Google Scholar The astrocytic end-foot process domain tightly enwraps the cerebral microvessels and at this level, contributes to the induction and maintenance of the blood-brain barrier (BBB), uptake of nutrients from the capillaries, and transport of K+ and water.4MacAulay N Hamann S Zeuthen T Water transport in the brain: role of cotransporters.Neuroscience. 2004; 129: 1031-1044Crossref PubMed Scopus (93) Google Scholar Because of the tight relationship between the astrocytes and the brain capillaries, astrocytes may deliver glucose to neurons within their own territory.1Nedergaard M Ransom B Goldman SA New roles for astrocytes: redefining the functional architecture of the brain.Trends Neurosci. 2003; 26: 523-530Abstract Full Text Full Text PDF PubMed Scopus (989) Google Scholar Astrocytes are extensively connected by gap junctions, forming a syncytiumlike organization.5Giaume C McCarthy KD Control of gap-junctional communication in astrocytic networks.Trends NeuroSci. 1996; 19: 319-325Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar Gap junctions are aqueous channels that connect the cytoplasm of adjoining cells. Each cell membrane contributes a hemichannel to each gap junction. The major constituent of these hemichannels is connexin 43. The astrocytic gap junctions and hemichannels are permeable to positively or negatively charged molecules. The gap junctions allow cell-cell communication, whereas nonjunctional hemichannels may allow passage of adenosine triphosphate (ATP) and other molecules into the extracellular space, which may mediate autocrine and paracrine signaling.6Bennett MV Contreras JE Bukauskas FF Saez JC New roles for astrocytes: gap junction hemichannels have something to communicate.Trends NeuroSci. 2003; 26: 610-617Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar Both gap junctions and hemichannels undergo short-term regulation by changes in channel gating and long-term regulation through changes in connexin 43 expression. Several influences affect permeability of gap junctions and hemichannels in astrocytes.5Giaume C McCarthy KD Control of gap-junctional communication in astrocytic networks.Trends NeuroSci. 1996; 19: 319-325Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar For example, intracellular acidification, large increases in intracellular Ca2+, activation of ATP-sensitive K+ channels, endothelin, and arachidonic acid reduce gap junction permeability. Hemichannels have a relatively low open permeability under physiological conditions but tend to be opened at relatively depolarized membrane potentials and low extracellular Ca2+. Although regulation of hemichannel and gap junction permeability has been shown primarily in vitro, it also may occur in human brain. If so, these mechanisms could be affected in metabolic, ischemic, or inflammatory conditions, resulting in impaired communication within the astrocyte network or cell death. Although the primary substrate of the BBB is the presence of tight junctions between endothelial cells, the astrocytic end-feet release signals that support the formation and the maintenance of these junctions as well as the expression of transport molecules in endothelial cells, including glucose transporter (GLUT) 1 for glucose.7Janzer RC Raff MC Astrocytes induce blood-brain barrier properties in endothelial cells.Nature. 1987; 325: 253-257Crossref PubMed Scopus (1300) Google Scholar, 8Abbott NJ Astrocyte-endothelial interactions and blood-brain barrier permeability.J Anat. 2002; 200: 629-638Crossref PubMed Scopus (920) Google Scholar, 9Magistretti PJ Pellerin L Rothman DL Shulman RG Energy on demand.Science. 1999; 283: 496-497Crossref PubMed Scopus (1006) Google Scholar Astrocytes also have an active role in the short-term modulation of BBB permeability. For example, in pathological conditions, astrocytes may release ATP, cytokines, glutamate, or nitric oxide (NO), which can increase BBB permeability.8Abbott NJ Astrocyte-endothelial interactions and blood-brain barrier permeability.J Anat. 2002; 200: 629-638Crossref PubMed Scopus (920) Google Scholar In immune or infectious disorders, these mediators may be released not only by astrocytes but also by activated microglial cells and may have a critical role in the development of cerebral edema and neuronal dysfunction. Perisynaptic astrocytic processes ensheathe the central excitatory synapses, extend into the synaptic cleft, and express clusters of glutamate receptors and transporters. Glutamate binding to these molecules triggers complex bidirectional neuron-astrocyte interactions that affect energy metabolism, excitability, and transmission of signals within and between the neuronal and astrocytic networks (Figure 2).10Bezzi P Domercq M Vesce S Volterra A Neuron-astrocyte cross-talk during synaptic transmission: physiological and neuropathological implications.Prog Brain Res. 2001; 132: 255-265Crossref PubMed Scopus (89) Google Scholar, 11Newman EA New roles for astrocytes: regulation of synaptic transmission.Trends Neurosci. 2003; 26: 536-542Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 12Haydon PG GLIA: listening and talking to the synapse.Nat Rev Neurosci. 2001; 2: 185-193Crossref PubMed Scopus (1161) Google Scholar, 13Hertz L Zielke HR Astrocytic control of glutamatergic activity: astrocytes as stars of the show.Trends NeuroSci. 2004; 27: 735-743Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar Glutamate is responsible for most of the fast excitatory synaptic transmission within the central nervous system. Astrocytes express several types of glutamate receptors, including ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate (NMDA) receptors and metabotropic glutamate receptors.10Bezzi P Domercq M Vesce S Volterra A Neuron-astrocyte cross-talk during synaptic transmission: physiological and neuropathological implications.Prog Brain Res. 2001; 132: 255-265Crossref PubMed Scopus (89) Google Scholar, 11Newman EA New roles for astrocytes: regulation of synaptic transmission.Trends Neurosci. 2003; 26: 536-542Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 14Verkhratsky A Steinhauser C Ion channels in glial cells.Brain Res Brain Res Rev. 2000; 32: 380-412Crossref PubMed Scopus (410) Google Scholar Glutamate released from excitatory synapses elicits depolarization and increase in intracellular Ca2+ ([Ca2+]i) in the astrocytes.10Bezzi P Domercq M Vesce S Volterra A Neuron-astrocyte cross-talk during synaptic transmission: physiological and neuropathological implications.Prog Brain Res. 2001; 132: 255-265Crossref PubMed Scopus (89) Google Scholar, 12Haydon PG GLIA: listening and talking to the synapse.Nat Rev Neurosci. 2001; 2: 185-193Crossref PubMed Scopus (1161) Google Scholar The main mechanism of glutamate-induced increase in [Ca2+]i in these cells is via activation of metabotropic glutamate receptor 5, triggering production of inositol triphosphate (IP3). Activation of IP3 receptors elicits mobilization of Ca2+ from the endoplasmic reticulum, and this increase in [Ca2+]i triggers a signaling process within the astrocytic network.15Verkhratsky A Kettenmann H Calcium signalling in glial cells.Trends Neurosci. 1996; 19: 346-352Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar This occurs via repetitive [Ca2+]i oscillations within individual astrocytes, which trigger Ca2+ waves that propagate to reach variable distances throughout the astrocytic syncytium.15Verkhratsky A Kettenmann H Calcium signalling in glial cells.Trends Neurosci. 1996; 19: 346-352Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar, 16Simard M Nedergaard M The neurobiology of glia in the context of water and ion homeostasis.Neuroscience. 2004; 129: 877-896Crossref PubMed Scopus (438) Google Scholar The propagation of these [Ca2+]i waves critically depends on the presence of connexin 43 and has been classically considered to be mediated by Ca2+, IP3, or both signals propagated through gap junction channels.15Verkhratsky A Kettenmann H Calcium signalling in glial cells.Trends Neurosci. 1996; 19: 346-352Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar However, recent evidence indicates that propagation of the intercellular Ca2+ signal within the astrocyte network involves a paracrine mechanism mediated by ATP signaling via the extracellular fluid.16Simard M Nedergaard M The neurobiology of glia in the context of water and ion homeostasis.Neuroscience. 2004; 129: 877-896Crossref PubMed Scopus (438) Google Scholar Adenosine triphosphate may be released to the extracellular fluid via hemichannels and acts via P2Y-type receptors to activate IP3 production and Ca2+ release from intracellular IP3-sensitive stores in the neighboring astrocytes (Figure 2). Adenosine triphosphate, via IP3, elicits ATP release, thus providing regenerative properties to the Ca2+ waves. The hemichannels also allow the passage of nicotinamide adenine dinucleotide, which is transformed into cyclic adenosine diphosphate (ADP)-ribose by action of an ectoenzyme expressed in the astrocyte membrane. This metabolite crosses the cell membrane and acts on ryanodine receptors on the endoplasmic reticulum to trigger the release of Ca2+ in the cytoplasm.6Bennett MV Contreras JE Bukauskas FF Saez JC New roles for astrocytes: gap junction hemichannels have something to communicate.Trends NeuroSci. 2003; 26: 610-617Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar The Ca2+ signal triggers release of glutamate from the astrocyte, which appears to occur by exocytosis and to involve effects of prostaglandin E2.10Bezzi P Domercq M Vesce S Volterra A Neuron-astrocyte cross-talk during synaptic transmission: physiological and neuropathological implications.Prog Brain Res. 2001; 132: 255-265Crossref PubMed Scopus (89) Google Scholar, 12Haydon PG GLIA: listening and talking to the synapse.Nat Rev Neurosci. 2001; 2: 185-193Crossref PubMed Scopus (1161) Google Scholar However, in vitro studies suggest that glutamate also could be released through hemichannels in some conditions, such as metabolic inhibition or low extracellular Ca2+. Glutamate released from astrocytes may have an important role in modulation of excitatory and inhibitory synapses in the central nervous system, as suggested by several in vitro studies.11Newman EA New roles for astrocytes: regulation of synaptic transmission.Trends Neurosci. 2003; 26: 536-542Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 17Nedergaard M Direct signaling from astrocytes to neurons in cultures of mammalian brain cells.Science. 1994; 263: 1768-1771Crossref PubMed Scopus (850) Google Scholar Furthermore, astrocyte-derived glutamate may directly activate neighboring neurons via a paracrine mechanism or contribute to cell death in conditions of metabolic inhibition, such as hypoxia or ischemia. Thus, the excitatory signals in the brain are transmitted at a distance through 2 parallel and interactive networks, neuronal and astrocytic, involving synaptically released glutamate, intracellular Ca2+ waves, and paracrine interactions mediated by glutamate, ATP, cyclic ADP-ribose, and probably other signals. These signaling processes have been demonstrated primarily in vitro under nonphysiological conditions but also may occur in the human brain. This wave of excitation could participate in mechanisms of spreading depolarization, leading to depression of cortical neuronal function in pathologic conditions such as cerebral ischemia or migraine. The Ca2+ signal in astrocytes also triggers release of D-serine, homocysteic acid, and arginine, which can affect glutamatergic neurotransmission. The D-serine acts at the glycine allosteric site of the NMDA receptor and facilitates Ca2+ influx through this channel,18Baranano DE Ferris CD Snyder SH Atypical neural messengers.Trends NeuroSci. 2001; 24: 99-106Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar whereas homocysteic acid is an endogenous agonist of the NMDA receptor.16Simard M Nedergaard M The neurobiology of glia in the context of water and ion homeostasis.Neuroscience. 2004; 129: 877-896Crossref PubMed Scopus (438) Google Scholar Arginine serves as a substrate for neuronal NO synthase. Astrocytes have a critical role in regulation of the synaptic levels of glutamate (Figure 3).13Hertz L Zielke HR Astrocytic control of glutamatergic activity: astrocytes as stars of the show.Trends NeuroSci. 2004; 27: 735-743Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar, 19Amara SG Fontana AC Excitatory amino acid transporters: keeping up with glutamate.Neurochem Int. 2002; 41: 313-318Crossref PubMed Scopus (203) Google Scholar, 20Danbolt NC Glutamate uptake.Prog Neurobiol. 2001; 65: 1-105Crossref PubMed Scopus (3768) Google Scholar, 21Sonnewald U Qu H Aschner M Pharmacology and toxicology of astrocyte-neuron glutamate transport and cycling.J Pharmacol Exp Ther. 2002; 301: 1-6Crossref PubMed Scopus (69) Google Scholar The uptake of synaptic glutamate via the excitatory amino acid transporters (EAATs) EAAT1 and EAAT2 present in the astrocyte is the major mechanism preventing accumulation of glutamate in the synaptic space and thus protects neurons from excessive activation of their glutamate receptors and excitotoxic injury.13Hertz L Zielke HR Astrocytic control of glutamatergic activity: astrocytes as stars of the show.Trends NeuroSci. 2004; 27: 735-743Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar, 19Amara SG Fontana AC Excitatory amino acid transporters: keeping up with glutamate.Neurochem Int. 2002; 41: 313-318Crossref PubMed Scopus (203) Google Scholar, 20Danbolt NC Glutamate uptake.Prog Neurobiol. 2001; 65: 1-105Crossref PubMed Scopus (3768) Google Scholar, 21Sonnewald U Qu H Aschner M Pharmacology and toxicology of astrocyte-neuron glutamate transport and cycling.J Pharmacol Exp Ther. 2002; 301: 1-6Crossref PubMed Scopus (69) Google Scholar Glutamate uptake is driven by the electrochemical gradient of Na+, which is maintained by action of Na+,K+-adenosine triphosphatase (ATPase) and is therefore critically dependent on energy metabolism. Impairment of glutamate uptake by the astrocyte in the setting of ATP depletion, as occurs with hypoxia, ischemia, or hypoglycemia, is considered a primary mechanism of excessive accumulation of glutamate in the synaptic space, leading to neuronal injury. In the astrocyte, uptake of 1 molecule of glutamate is accompanied by cotransport of 3 Na+, 1 H+, and 1 Cl−, antiport of 1 K+ ion, and consumption of 1 ATP molecule.19Amara SG Fontana AC Excitatory amino acid transporters: keeping up with glutamate.Neurochem Int. 2002; 41: 313-318Crossref PubMed Scopus (203) Google Scholar, 20Danbolt NC Glutamate uptake.Prog Neurobiol. 2001; 65: 1-105Crossref PubMed Scopus (3768) Google Scholar These transporters also cotransport water, along with glutamate and cations, into the astrocye.4MacAulay N Hamann S Zeuthen T Water transport in the brain: role of cotransporters.Neuroscience. 2004; 129: 1031-1044Crossref PubMed Scopus (93) Google Scholar The increase in intracellular Na+ resulting from glutamate transport into the astrocytes has important metabolic consequences because it may serve as a signal that couples synaptic activity with glucose consumption (Figure 3).22Magistretti PJ Pellerin L Astrocytes couple synaptic activity to glucose utilization in the brain.News Physiol Sci. 1999; 14: 177-182PubMed Google Scholar Intracellular Na+ accumulation activates the Na+,K+-ATPase, and the resulting increase in the ADP/ATP ratio leads to activation of glycolysis. This process occurs in parallel with the propagation of Ca2+ waves in the astrocytic syncytium, which is mediated by ATP and triggers glutamate release. As glutamate released by this Ca2+ wave undergoes re-uptake via the glutamate-Na+ cotransporter, it triggers an intracellular astrocytic Na+ wave.23Bernardinelli Y Magistretti PJ Chatton J-Y Astrocytes generate Na+-mediated metabolic waves.Proc Natl Acad Sci U S A. 2004; 101: 14937-14942Crossref PubMed Scopus (163) Google Scholar This “metabolic wave” could propagate via gap junctions and trigger glycolysis in other astrocytes within the network, as discussed subsequently. However, it is still uncertain about whether it contributes to the mechanisms of coupling between neuronal activity and astrocyte metabolism in the healthy brain. In the astrocyte, glutamate serves both as a metabolic fuel and as precursor of glutamine and glutathione. The synthesis of glutamine in astrocytes is critical for 2 fundamental processes: replenishment of the glutamate pool in the neurons13Hertz L Zielke HR Astrocytic control of glutamatergic activity: astrocytes as stars of the show.Trends NeuroSci. 2004; 27: 735-743Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar and ammonia detoxification in the nervous system (Figure 3).24Marcaggi P Coles JA Ammonium in nervous tissue: transport across cell membranes, fluxes from neurons to glial cells, and role in signalling [published correction appears in Prog Neurobiol. 2001;65:209-210].Prog Neurobiol. 2001; 64: 157-183Crossref PubMed Scopus (91) Google Scholar Neurons, unlike astrocytes, cannot synthesize glutamate from glucose. Because they also have a deficient glutamate uptake mechanism, they depend on the supply of glutamine from the astrocytes in order to synthesize glutamate.13Hertz L Zielke HR Astrocytic control of glutamatergic activity: astrocytes as stars of the show.Trends NeuroSci. 2004; 27: 735-743Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar Since the brain lacks an effective urea cycle, astrocyte synthesis of glutamine is the major mechanism for ammonia detoxification in the nervous system.25Suarez I Bodega G Fernandez B Glutamine synthetase in brain: effect of ammonia.Neurochem Int. 2002; 41: 123-142Crossref PubMed Scopus (268) Google Scholar This reaction is catalyzed by glutamine synthetase, which is a biochemical marker of the astrocytes and synthesizes glutamine from glutamate and ammonia in the presence of ATP. Glutamine is transported from the astrocytes to the neurons, where it is transformed back to glutamate by action of the enzyme glutaminase. This glutamate-glutamine cycle between neurons and astrocytes is critical for replenishment of the neuronal glutamate pool for neurotransmission. In disorders affecting ammonia metabolism, such as hepatic failure or urea cycle defects, there is increased synthesis of glutamine from glutamate in the astrocytes. This results in morphologic and functional changes that contribute to cerebral edema and neuronal and astrocytic dysfunction in these conditions. Astrocytes, but not neurons, contain a cystine-glutamate exchanger.20Danbolt NC Glutamate uptake.Prog Neurobiol. 2001; 65: 1-105Crossref PubMed Scopus (3768) Google Scholar The function of this transporter is to accumulate cystine, which is reduced to cysteine for the production of glutathione in the astrocyte.26Dringen R Metabolism and functions of glutathione in brain.Prog Neurobiol. 2000; 62: 649-671Crossref PubMed Scopus (1332) Google Scholar In this process, astrocytes release glutamate to the extracellular space. Glutathione is an important antioxidant molecule, and its synthesis occurs primarily in the astrocyte. Astroglial glutathione export to the extracellular space is essential for providing the neurons with the glutathione precursor L-cysteinyl glycine formed from glutathione by the coenzyme γ-glutamyl transpeptidase.26Dringen R Metabolism and functions of glutathione in brain.Prog Neurobiol. 2000; 62: 649-671Crossref PubMed Scopus (1332) Google Scholar Oxidative stress is an important mechanism of neuronal injury in several neurologic disorders, including cerebral ischemia and neurodegenerative conditions; thus, production of glutathione by the astrocytes may have an important neuroprotective role. Astrocytes participate in the regulation of inhibitory GABAergic synapses. In astrocytes, unlike most mature neurons, activation of GABAA receptors elicits depolarization because of the presence of an inwardly directed Cl− transport in glial cells that affects the Cl− equilibrium potential.3Olson JE Li GZ Wang L Lu L Volume-regulated anion conductance in cultured rat cerebral astrocytes requires calmodulin activity.Glia. 2004; 46: 391-401Crossref PubMed Scopus (13) Google Scholar Astrocytes participate in the uptake of GABA.27Chatton JY Pellerin L Magistretti PJ GABA uptake into astrocytes is not associated with significant metabolic cost: implications for brain imaging of inhibitory transmission.Proc Natl Acad Sci U S A. 2003; 100: 12456-12461Crossref PubMed Scopus (151) Google Scholar Although they can utilize GABA to reconstitute glutamate, they cannot utilize glutamate to resynthesize GABA. In the astrocyte, glutamate is utilized for oxidative metabolism, glutamine synthesis, or exchange with cystine for production of glutathione. Thus, neuron-astrocyte interactions are important for maintaining a balance between excitatory and inhibitory synaptic transmission, which is critical to regulate neuronal excitability in the central nervous system. Disruption of this balance may have a relevant role in mechanisms of abnormal neuronal activity that occurs in seizures. Glucose entering the brain is first transported by the endothelial cells and astrocytic end-foot processes via the GLUT-1. Glucose also may enter the neurons directly via GLUT-3.28Chih CP Lipton P Roberts Jr, EL Do active cerebral neurons really use lactate rather than glucose?.Trends Neurosci. 2001; 24: 573-578Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar Glucose transport across the BBB may be adapted dynamically to the increase in glucose consumption that results from neuronal activity.29Leybaert L Neurobarrier coupling in the brain: a partner of neurovascular and neurometabolic coupling?.J Cereb Blood Flow Metab. 2005; 25: 2-16PubMed Google Scholar In the astrocyte, glucose is used for synthesis of glycogen and glycolysis with production of lactic acid (Figure 3). Glycogen turnover in astrocytes increases with enhanced neuronal activity to provide extra energy supply to the neuron. Both L-glutamate and insulin have been shown to increase glycogen synthesis in astrocytes in vitro. Glycogen may have a critical role in supporting neurons and axons in conditions such as hypoglycemia.30Brown AM Brain glycogen re-awakened.J Neurochem. 2004; 89: 537-552Crossref PubMed Scopus (248) Google Scholar As in the liver, adrenergic inputs acting via β-receptors activate glycogenolysis in astrocytes. However, the main product of glycogen breakdown in astrocytes is not glucose but lactic acid. Astrocytes transform pyruvate into lactic acid by the action of the lactate dehydrogenase (LDH) isoenzyme LDH5.22Magistretti PJ Pellerin L Astrocytes couple synaptic activity to glucose utilization in the brain.News Physiol Sci. 1999; 14: 177-182PubMed Google Scholar Lactate is transported out of the astrocyte via the H+-coupled monocarboxylate transporters (MCTs) MCT1 and MCT4 and is taken up by neurons via MCT2. In neurons, lactate is converted to pyruvate by the action of LDH1, and pyruvate can serve as a substrate for oxidative metabolism. This astrocyte-neuron lactate shuttle mechanism has been proposed to be critical for metabolic support of neurons during synaptic activity.22Magistretti PJ Pellerin L Astrocytes couple synaptic activity to glucose utilization in the brain.News Physiol Sci. 1999; 14: 177-182PubMed Google Scholar However, it has also been argued that glucose, rather than lactate, may be the primary source of energy during neuronal activity. Although neuronal processes are not in direct contact with capillaries, glucose is readily available to neurons at levels sufficient for optimal activity of glycolytic enzymes. Glucose metabolism in the brain may be affected in diabetes mellitus.31McCall AL Cerebral glucose metabolism in diabetes
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