The main energy source powering the brain is glucose. Strong energy needs of our nervous system are fulfilled by conveying this essential metabolite through blood via an extensive vascular network. Glucose then reaches brain tissues by cell uptake, diffusion and metabolization, processes primarily undertaken by astrocytes. Deprivation of glucose can however occur in various circumstances. In particular, ageing is associated with cognitive disturbances that are partly attributable to metabolic deficiency leading to brain glycopenia. Despite the crucial role of glucose and its metabolites in sustaining neuronal activity, little is known about its moment-to-moment contribution to astroglial physiology. We thus here investigated the early structural and functional alterations induced in astrocytes by a transient metabolic challenge consisting in glucose deprivation. Electrophysiological recordings of hippocampal astroglial cells of the stratum radiatum in situ revealed that shortage of glucose specifically increases astrocyte membrane capacitance, whilst it has no impact on other passive membrane properties. Consistent with this change, morphometric analysis unraveled a prompt increase in astrocyte volume upon glucose deprivation. Furthermore, characteristic functional properties of astrocytes are also affected by transient glucose deficiency. We indeed found that glucoprivation decreases their gap junction-mediated coupling, while it progressively and reversibly increases their intracellular calcium levels during the slow depression of synaptic transmission occurring simultaneously, as assessed by dual electrophysiological and calcium imaging recordings. Together, these data indicate that astrocytes rapidly respond to metabolic dysfunctions, and are therefore central to the neuroglial dialog at play in brain adaptation to glycopenia.

Department of Cellular Neurophysiology Institute of Experimental Medicine Academy of Sciences of the Czech RepublicPrague Czech Republic; Department of Neuroscience 2nd Faculty of Medicine Charles UniversityPrague Czech Republic

Neuroglial Interactions in Cerebral Physiopathology Center for Interdisciplinary Research in Biology Collège de France Centre National de la Recherche Scientifique UMR 7241 Institut National de la Santé et de la Recherche Médicale U1050 Labex Memolife PSL Research University Paris France

Zobrazit více v PubMed

Abdelhafiz A. H., Rodriguez-Manas L., Morley J. E., Sinclair A. J. (2015). Hypoglycemia in older people - a less well recognized risk factor for frailty. Aging Dis. 6, 156–167. 10.14336/ad.2014.0330 PubMed DOI PMC

Allaman I., Belanger M., Magistretti P. J. (2011). Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci. 34, 76–87. 10.1016/j.tins.2010.12.001 PubMed DOI

Anderova M., Benesova J., Mikesova M., Dzamba D., Honsa P., Kriska J., et al. . (2014). Altered astrocytic swelling in the cortex of alpha-syntrophin-negative GFAP/EGFP mice. PLoS One 9:e113444. 10.1371/journal.pone.0113444 PubMed DOI PMC

Andrew R. D., Lobinowich M. E., Osehobo E. P. (1997). Evidence against volume regulation by cortical brain cells during acute osmotic stress. Exp. Neurol. 143, 300–312. 10.1006/exnr.1996.6375 PubMed DOI

Arluison M., Quignon M., Nguyen P., Thorens B., Leloup C., Penicaud L. (2004). Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brain—an immunohistochemical study. J. Chem. Neuroanat. 28, 117–136. 10.1016/j.jchemneu.2004.05.009 PubMed DOI

Arnold S. (2005). Estrogen suppresses the impact of glucose deprivation on astrocytic calcium levels and signaling independently of the nuclear estrogen receptor. Neurobiol. Dis. 20, 82–92. 10.1016/j.nbd.2005.02.002 PubMed DOI

Ball K. K., Harik L., Gandhi G. K., Cruz N. F., Dienel G. A. (2011). Reduced gap junctional communication among astrocytes in experimental diabetes: contributions of altered connexin protein levels and oxidative-nitrosative modifications. J. Neurosci. Res. 89, 2052–2067. 10.1002/jnr.22663 PubMed DOI PMC

Barros L. F., Courjaret R., Jakoby P., Loaiza A., Lohr C., Deitmer J. W. (2009). Preferential transport and metabolism of glucose in Bergmann glia over Purkinje cells: a multiphoton study of cerebellar slices. Glia 57, 962–970. 10.1002/glia.20820 PubMed DOI

Benesova J., Hock M., Butenko O., Prajerova I., Anderova M., Chvatal A. (2009). Quantification of astrocyte volume changes during ischemia in situ reveals two populations of astrocytes in the cortex of GFAP/EGFP mice. J. Neurosci. Res. 87, 96–111. 10.1002/jnr.21828 PubMed DOI

Benesova J., Rusnakova V., Honsa P., Pivonkova H., Dzamba D., Kubista M., et al. . (2012). Distinct expression/function of potassium and chloride channels contributes to the diverse volume regulation in cortical astrocytes of GFAP/EGFP mice. PLoS One 7:e29725. 10.1371/journal.pone.0029725 PubMed DOI PMC

Boury-Jamot B., Carrard A., Martin J. L., Halfon O., Magistretti P. J., Boutrel B. (2015). Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine. Mol. Psychiatry [Epub ahead of print]. . 10.1038/mp.2015.157 PubMed DOI PMC

Brown A. M. (2004). Brain glycogen re-awakened. J. Neurochem. 89, 537–552. 10.1111/j.1471-4159.2004.02421.x PubMed DOI

Brown A. M., Sickmann H. M., Fosgerau K., Lund T. M., Schousboe A., Waagepetersen H. S., et al. . (2005). Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter. J. Neurosci. Res. 79, 74–80. 10.1002/jnr.20335 PubMed DOI

Chever O., Pannasch U., Ezan P., Rouach N. (2014). Astroglial connexin 43 sustains glutamatergic synaptic efficacy. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369:20130596. 10.1098/rstb.2013.0596 PubMed DOI PMC

Dallérac G., Rouach N. (2016). Astrocytes as new targets to improve cognitive functions. Prog. Neurobiol. [Epub ahead of print]. 10.1016/j.pneurobio.2016.01.003 PubMed DOI

Du Y., Ma B., Kiyoshi C. M., Alford C. C., Wang W., Zhou M. (2015). Freshly dissociated mature hippocampal astrocytes exhibit passive membrane conductance and low membrane resistance similarly to syncytial coupled astrocytes. J. Neurophysiol. 113, 3744–3750. 10.1152/jn.00206.2015 PubMed DOI PMC

Escartin C., Rouach N. (2013). Astroglial networking contributes to neurometabolic coupling. Front. Neuroenergetics 5:4. 10.3389/fnene.2013.00004 PubMed DOI PMC

Fernández-Moncada I., Barros L. F. (2014). Non-preferential fuelling of the Na+/K+-ATPase pump. Biochem. J. 460, 353–361. 10.1042/bj20140003 PubMed DOI

Gandhi G. K., Ball K. K., Cruz N. F., Dienel G. A. (2010). Hyperglycaemia and diabetes impair gap junctional communication among astrocytes. ASN Neuro. 2:e00030. 10.1042/an20090048 PubMed DOI PMC

Harris J. J., Jolivet R., Attwell D. (2012). Synaptic energy use and supply. Neuron 75, 762–777. 10.1016/j.neuron.2012.08.019 PubMed DOI

Hermann G. E., Viard E., Rogers R. C. (2014). Hindbrain glucoprivation effects on gastric vagal reflex circuits and gastric motility in the rat are suppressed by the astrocyte inhibitor fluorocitrate. J. Neurosci. 34, 10488–10496. 10.1523/jneurosci.1406-14.2014 PubMed DOI PMC

Hirase H., Qian L., Bartho P., Buzsaki G. (2004). Calcium dynamics of cortical astrocytic networks in vivo. PLoS Biol. 2:E96. 10.1371/journal.pbio.0020096 PubMed DOI PMC

Hirrlinger J., Hulsmann S., Kirchhoff F. (2004). Astroglial processes show spontaneous motility at active synaptic terminals in situ. Eur. J. Neurosci. 20, 2235–2239. 10.1111/j.1460-9568.2004.03689.x PubMed DOI

Howarth C., Gleeson P., Attwell D. (2012). Updated energy budgets for neural computation in the neocortex and cerebellum. J. Cereb. Blood Flow Metab. 32, 1222–1232. 10.1038/jcbfm.2012.35 PubMed DOI PMC

Hwang E. M., Kim E., Yarishkin O., Woo D. H., Han K. S., Park N., et al. . (2014). A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes. Nat. Commun. 5:3227. 10.1038/ncomms4227 PubMed DOI

Ioudina M., Uemura E., Greenlee H. W. (2004). Glucose insufficiency alters neuronal viability and increases susceptibility to glutamate toxicity. Brain Res. 1004, 188–192. 10.1016/j.brainres.2003.12.046 PubMed DOI

Itoh Y., Abe T., Takaoka R., Tanahashi N. (2004). Fluorometric determination of glucose utilization in neurons in vitro and in vivo. J. Cereb. Blood Flow Metab. 24, 993–1003. 10.1097/01.wcb.0000127661.07591.de PubMed DOI

Jakoby P., Schmidt E., Ruminot I., Gutiérrez R., Barros L. F., Deitmer J. W. (2014). Higher transport and metabolism of glucose in astrocytes compared with neurons: a multiphoton study of hippocampal and cerebellar tissue slices. Cereb. Cortex 24, 222–231. 10.1093/cercor/bhs309 PubMed DOI

Kacem K., Lacombe P., Seylaz J., Bonvento G. (1998). Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study. Glia 23, 1–10. 10.1002/(sici)1098-1136(199805)23:1<1::aid-glia1>3.0.co;2-b PubMed DOI

Khakh B. S., Mccarthy K. D. (2015). Astrocyte calcium signaling: from observations to functions and the challenges therein. Cold Spring Harb. Perspect. Biol. 7:a020404. 10.1101/cshperspect.a020404 PubMed DOI PMC

Korol D. L., Gold P. E. (1998). Glucose, memory and aging. Am. J. Clin. Nutr. 67, 764S–771S. PubMed

Lieth E., Barber A. J., Xu B., Dice C., Ratz M. J., Tanase D., et al. . (1998). Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Penn State Retina Research Group. Diabetes 47, 815–820. 10.2337/diabetes.47.5.815 PubMed DOI

Lipton P. (1999). Ischemic cell death in brain neurons. Physiol. Rev. 79, 1431–1568. 10.1203/00006450-199904020-00260 PubMed DOI

Lord L. D., Expert P., Huckins J. F., Turkheimer F. E. (2013). Cerebral energy metabolism and the brain’s functional network architecture: an integrative review. J. Cereb. Blood Flow Metab. 33, 1347–1354. 10.1038/jcbfm.2013.94 PubMed DOI PMC

Lundgaard I., Li B., Xie L., Kang H., Sanggaard S., Haswell J. D., et al. . (2015). Direct neuronal glucose uptake Heralds activity-dependent increases in cerebral metabolism. Nat. Commun. 6:6807. 10.1038/ncomms7807 PubMed DOI PMC

Lutz S. E., Zhao Y., Gulinello M., Lee S. C., Raine C. S., Brosnan C. F. (2009). Deletion of astrocyte connexins 43 and 30 leads to a dysmyelinating phenotype and hippocampal CA1 vacuolation. J. Neurosci. 29, 7743–7752. 10.1523/jneurosci.0341-09.2009 PubMed DOI PMC

Magistretti P. J., Allaman I. (2015). A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901. 10.1016/j.neuron.2015.03.035 PubMed DOI

McDougal D. H., Hermann G. E., Rogers R. C. (2013). Astrocytes in the nucleus of the solitary tract are activated by low glucose or glucoprivation: evidence for glial involvement in glucose homeostasis. Front. Neurosci. 7:249. 10.3389/fnins.2013.00249 PubMed DOI PMC

McNay E. C. (2005). The impact of recurrent hypoglycemia on cognitive function in aging. Neurobiol. Aging 26 Suppl 1, 76–79. 10.1016/j.neurobiolaging.2005.08.014 PubMed DOI

McNay E. C., Gold P. E. (2001). Age-related differences in hippocampal extracellular fluid glucose concentration during behavioral testing and following systemic glucose administration. J. Gerontol. A. Biol. Sci. Med. Sci. 56, B66–B71. 10.1093/gerona/56.2.b66 PubMed DOI

Medrano S., Gruenstein E., Dimlich R. V. (1992). Histamine stimulates glycogenolysis in human astrocytoma cells by increasing intracellular free calcium. Brain Res. 592, 202–207. 10.1016/0006-8993(92)91677-7 PubMed DOI

Mergenthaler P., Lindauer U., Dienel G. A., Meisel A. (2013). Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 36, 587–597. 10.1016/j.tins.2013.07.001 PubMed DOI PMC

Nehlig A., Wittendorp-Rechenmann E., Lam C. D. (2004). Selective uptake of [14C]2-deoxyglucose by neurons and astrocytes: high-resolution microautoradiographic imaging by cellular 14C-trajectography combined with immunohistochemistry. J. Cereb. Blood Flow Metab. 24, 1004–1014. 10.1097/01.wcb.0000128533.84196.d8 PubMed DOI

Nielsen S., Nagelhus E. A., Amiry-Moghaddam M., Bourque C., Agre P., Ottersen O. P. (1997). Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J. Neurosci. 17, 171–180. PubMed PMC

Nolte C., Matyash M., Pivneva T., Schipke C. G., Ohlemeyer C., Hanisch U. K., et al. . (2001). GFAP promoter-controlled EGFP-expressing transgenic mice: a tool to visualize astrocytes and astrogliosis in living brain tissue. Glia 33, 72–86. 10.1002/1098-1136(20010101)33:1<72::aid-glia1007>n3.3.co;2-1 PubMed DOI

Pannasch U., Freche D., Dallerac G., Ghezali G., Escartin C., Ezan P., et al. . (2014). Connexin 30 sets synaptic strength by controlling astroglial synapse invasion. Nat. Neurosci. 17, 549–558. 10.1038/nn.3662 PubMed DOI

Pannasch U., Vargova L., Reingruber J., Ezan P., Holcman D., Giaume C., et al. . (2011). Astroglial networks scale synaptic activity and plasticity. Proc. Natl. Acad. Sci. U S A 108, 8467–8472. 10.1073/pnas.1016650108 PubMed DOI PMC

Papadopoulos M. C., Koumenis I. L., Dugan L. L., Giffard R. G. (1997). Vulnerability to glucose deprivation injury correlates with glutathione levels in astrocytes. Brain Res. 748, 151–156. 10.1016/s0006-8993(96)01293-0 PubMed DOI

Pascual O., Casper K. B., Kubera C., Zhang J., Revilla-Sanchez R., Sul J. Y., et al. . (2005). Astrocytic purinergic signaling coordinates synaptic networks. Science 310, 113–116. 10.1126/science.1116916 PubMed DOI

Patel A. B., Lai J. C. K., Chowdhury G. M. I., Hyder F., Rothman D. L., Shulman R. G., et al. . (2014). Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle. Proc. Natl. Acad. Sci. USA 111, 5385–5390. 10.1073/pnas.1403576111 PubMed DOI PMC

Penicaud L., Leloup C., Fioramonti X., Lorsignol A., Benani A. (2006). Brain glucose sensing: a subtle mechanism. Curr. Opin. Clin. Nutr. Metab. Care. 9, 458–462. 10.1097/01.mco.0000232908.84483.e0 PubMed DOI

Rouach N., Koulakoff A., Abudara V., Willecke K., Giaume C. (2008). Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551–1555. 10.1126/science.1164022 PubMed DOI

Sahu G., Sukumaran S., Bera A. K. (2014). Pannexins form gap junctions with electrophysiological and pharmacological properties distinct from connexins. Sci. Rep. 4:4955. 10.1038/srep04955 PubMed DOI PMC

Salameh A., Dhein S. (2013). Effects of mechanical forces and stretch on intercellular gap junction coupling. Biochim. Biophys. Acta 1828, 147–156. 10.1016/j.bbamem.2011.12.030 PubMed DOI

Saravia F. E., Revsin Y., Gonzalez Deniselle M. C., Gonzalez S. L., Roig P., Lima A., et al. . (2002). Increased astrocyte reactivity in the hippocampus of murine models of type 1 diabetes: the nonobese diabetic (NOD) and streptozotocin-treated mice. Brain Res. 957, 345–353. 10.1016/s0006-8993(02)03675-2 PubMed DOI

Schools G. P., Zhou M., Kimelberg H. K. (2006). Development of gap junctions in hippocampal astrocytes: evidence that whole cell electrophysiological phenotype is an intrinsic property of the individual cell. J. Neurophysiol. 96, 1383–1392. 10.1152/jn.00449.2006 PubMed DOI

Schurr A., Miller J. J., Payne R. S., Rigor B. M. (1999). An increase in lactate output by brain tissue serves to meet the energy needs of glutamate-activated neurons. J. Neurosci. 19, 34–39. PubMed PMC

Shulman R. G., Rothman D. L., Behar K. L., Hyder F. (2004). Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci. 27, 489–495. 10.1016/j.tins.2004.06.005 PubMed DOI

Silver I. A., Deas J., Erecinska M. (1997). Ion homeostasis in brain cells: differences in intracellular ion responses to energy limitation between cultured neurons and glial cells. Neuroscience 78, 589–601. 10.1016/s0306-4522(96)00600-8 PubMed DOI

Simard M., Arcuino G., Takano T., Liu Q. S., Nedergaard M. (2003). Signaling at the gliovascular interface. J. Neurosci. 23, 9254–9262. PubMed PMC

Smith A. J., Verkman A. S. (2015). Superresolution imaging of aquaporin-4 cluster size in antibody-stained paraffin brain sections. Biophys. J. 109, 2511–2522. 10.1016/j.bpj.2015.10.047 PubMed DOI PMC

Stolarczyk E., Guissard C., Michau A., Even P. C., Grosfeld A., Serradas P., et al. . (2010). Detection of extracellular glucose by GLUT2 contributes to hypothalamic control of food intake. Am. J. Physiol. Endocrinol. Metab. 298, E1078–E1087. 10.1152/ajpendo.00737.2009 PubMed DOI

Sun D., Jakobs T. C. (2012). Structural remodeling of astrocytes in the injured CNS. Neuroscientist 18, 567–588. 10.1177/1073858411423441 PubMed DOI PMC

Suzuki A., Stern S. A., Bozdagi O., Huntley G. W., Walker R. H., Magistretti P. J., et al. . (2011). Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144, 810–823. 10.1016/j.cell.2011.02.018 PubMed DOI PMC

Sykova E. (2001). Glial diffusion barriers during aging and pathological states. Prog. Brain Res. 132, 339–363. 10.1016/s0079-6123(01)32087-3 PubMed DOI

Sykova E., Mazel T., Hasenohrl R. U., Harvey A. R., Simonova Z., Mulders W. H., et al. . (2002). Learning deficits in aged rats related to decrease in extracellular volume and loss of diffusion anisotropy in hippocampus. Hippocampus 12, 269–279. 10.1002/hipo.1101 PubMed DOI

Tsacopoulos M., Magistretti P. J. (1996). Metabolic coupling between glia and neurons. J. Neurosci. 16, 877–885. PubMed PMC

Wang D., Pascual J. M., Yang H., Engelstad K., Jhung S., Sun R. P., et al. . (2005). Glut-1 deficiency syndrome: clinical, genetic and therapeutic aspects. Ann. Neurol. 57, 111–118. 10.1002/ana.20331 PubMed DOI

Wender R., Brown A. M., Fern R., Swanson R. A., Farrell K., Ransom B. R. (2000). Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J. Neurosci. 20, 6804–6810. PubMed PMC

Winkler E. A., Nishida Y., Sagare A. P., Rege S. V., Bell R. D., Perlmutter D., et al. (2015). GLUT1 redsuctions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat. Neurosci. 18, 521–530. 10.1038/nn.3966 PubMed DOI PMC

Zhou M., Xu G., Xie M., Zhang X., Schools G. P., Ma L., et al. . (2009). TWIK-1 and TREK-1 are potassium channels contributing significantly to astrocyte passive conductance in rat hippocampal slices. J. Neurosci. 29, 8551–8564. 10.1523/jneurosci.5784-08.2009 PubMed DOI PMC