Abstract
Glutamate is the most abundant neurotransmitter of the central nervous system, as the majority of neurons use glutamate as neurotransmitter. It is also well known that this neurotransmitter is not restricted to synaptic clefts, but found in the extrasynaptic regions as ambient glutamate. Extrasynaptic glutamate originates from spillover of synaptic release, as well as from astrocytes and microglia. Its concentration is magnitudes lower than in the synaptic cleft, but receptors responding to it have higher affinity for it. Extrasynaptic glutamate receptors can be found in neuronal somatodendritic location, on astroglia, oligodendrocytes or microglia. Activation of them leads to changes of neuronal excitability with different amplitude and kinetics. Extrasynaptic glutamate is taken up by neurons and astrocytes mostly via EAAT transporters, and astrocytes, in turn metabolize it to glutamine. Extrasynaptic glutamate is involved in several physiological phenomena of the central nervous system. It regulates neuronal excitability and synaptic strength by involving astroglia; contributing to learning and memory formation, neurosecretory and neuromodulatory mechanisms, as well as sleep homeostasis.The extrasynaptic glutamatergic system is affected in several brain pathologies related to excitotoxicity, neurodegeneration or neuroinflammation. Being present in dementias, neurodegenerative and neuropsychiatric diseases or tumor invasion in a seemingly uniform way, the system possibly provides a common component of their pathogenesis. Although parts of the system are extensively discussed by several recent reviews, in this review I attempt to summarize physiological actions of the extrasynaptic glutamate on neuronal excitability and provide a brief insight to its pathology for basic understanding of the topic.
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References
Szapiro G, Barbour B (2009) Parasynaptic signalling by fast neurotransmitters: the cerebellar cortex. Neuroscience 162(3):644–655. https://doi.org/10.1016/j.neuroscience.2009.03.077
Petralia RS, Wang YX, Hua F, Yi Z, Zhou A, Ge L, Stephenson FA, Wenthold RJ (2010) Organization of NMDA receptors at extrasynaptic locations. Neuroscience 167(1):68–87. https://doi.org/10.1016/j.neuroscience.2010.01.022
Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11(10):682–696. https://doi.org/10.1038/nrn2911
Papouin T, Oliet SH (2014) Organization, control and function of extrasynaptic NMDA receptors. Philos Trans R Soc Lond B Biol Sci. 369(1654):20130601. https://doi.org/10.1098/rstb.2013.0601
Rodriguez M, Sabate M, Rodriguez-Sabate C, Morales I (2013) The role of non-synaptic extracellular glutamate. Brain Res Bull 93:17–26. https://doi.org/10.1016/j.brainresbull.2012.09.018
Kullmann DM, Erdemli G, Asztély F (1996) LTP of AMPA and NMDA receptor-mediated signals: evidence for presynaptic expression and extrasynaptic glutamate spill-over. Neuron 17(3):461–474
Asztely F, Erdemli G, Kullmann DM (1997) Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake. Neuron 18(2):281–293
Rusakov DA, Kullmann DM (1998) Geometric and viscous components of the tortuosity of the extracellular space in the brain. Proc Natl Acad Sci USA. 95(15):8975–8980
Chalifoux JR, Carter AG (2011) Glutamate spillover promotes the generation of NMDA spikes. J Neurosci 31(45):16435–16446. https://doi.org/10.1523/jneurosci.2777-11.2011
Kullmann DM, Asztely F (1998) Extrasynaptic glutamate spillover in the hippocampus: evidence and implications. Trends Neurosci 21(1):8–14
Nie H, Weng HR (2009) Glutamate transporters prevent excessive activation of NMDA receptors and extrasynaptic glutamate spillover in the spinal dorsal horn. J Neurophysiol 101(4):2041–2051. https://doi.org/10.1152/jn.91138.2008
Oikonomou KD, Singh MB, Rich MT, Short SM, Antic SD (2015) Contribution of extrasynaptic N-methyl-d-aspartate and adenosine A1 receptors in the generation of dendritic glutamate-mediated plateau potentials. Philos Trans R Soc Lond B Biol Sci. https://doi.org/10.1098/rstb.2014.0193
Shen HW, Scofield MD, Boger H, Hensley M, Kalivas PW (2014) Synaptic glutamate spillover due to impaired glutamate uptake mediates heroin relapse. J Neurosci 34(16):5649–5657. https://doi.org/10.1523/jneurosci.4564-13.2014
Marcoli M, Agnati LF, Benedetti F, Genedani S, Guidolin D, Ferraro L, Maura G, Fuxe K (2015) On the role of the extracellular space on the holistic behavior of the brain. Rev Neurosci 26(5):489–506. https://doi.org/10.1515/revneuro-2015-0007
Syková E, Vargová L (2008) Extrasynaptic transmission and the diffusion parameters of the extracellular space. Neurochem Int 52(1–2):5–13
Rimmele TS, Rocher AB, Wellbourne-Wood J, Chatton JY (2017) Control of glutamate transport by extracellular potassium: basis for a negative feedback on synaptic transmission. Cereb Cortex 27(6):3272–3283. https://doi.org/10.1093/cercor/bhx078
Wild AR, Bollands M, Morris PG, Jones S (2015) Mechanisms regulating spill-over of synaptic glutamate to extrasynaptic NMDA receptors in mouse substantia nigra dopaminergic neurons. Eur J Neurosci 42(9):2633–2643. https://doi.org/10.1111/ejn.13075
Armbruster M, Hanson E, Dulla CG (2016) Glutamate clearance is locally modulated by presynaptic neuronal activity in the cerebral cortex. J Neurosci 36(40):10404–10415
Del Arco A, Segovia G, Fuxe K, Mora F (2003) Changes in dialysate concentrations of glutamate and GABA in the brain: an index of volume transmission mediated actions? J Neurochem 85(1):23–33
Matsui K, Jahr CE (2003) Ectopic release of synaptic vesicles. Neuron 40(6):1173–1183
Matsui K, Jahr CE (2004) Differential control of synaptic and ectopic vesicular release of glutamate. J Neurosci 24(41):8932–8939
Matsui K, Jahr CE, Rubio ME (2005) High-concentration rapid transients of glutamate mediate neural-glial communication via ectopic release. J Neurosci 25(33):7538–7547
Balakrishnan S, Dobson KL, Jackson C, Bellamy TC (2014) Ectopic release of glutamate contributes to spillover at parallel fibre synapses in the cerebellum. J Physiol 592(7):1493–1503. https://doi.org/10.1113/jphysiol.2013.267039
Rossi DJ, Oshima T, Attwell D (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403(6767):316–321
La Bella V, Valentino F, Piccoli T, Piccoli F (2007) Expression and developmental regulation of the cystine/glutamateexchanger (xc-) in the rat. Neurochem Res 32(6):1081–1090
Soria FN, Zabala A, Pampliega O, Palomino A, Miguelez C, Ugedo L, Sato H, Matute C, Domercq M (2016) Cystine/glutamate antiporter blockage induces myelin degeneration. Glia. 64(8):1381–1395. https://doi.org/10.1002/glia.23011
Wendt S, Wogram E, Korvers L, Kettenmann H (2016) Experimental cortical spreading depression induces NMDA receptor dependent potassium currents in microglia. J Neurosci 36(23):6165–6174. https://doi.org/10.1523/jneurosci.4498-15.2016
Malarkey EB, Parpura V (2008) Mechanisms of glutamate release from astrocytes. Neurochem Int 52(1–2):142–154
Panatier A, Robitaille R (2016) Astrocytic mGluR5 and the tripartite synapse. Neuroscience 323:29–34. https://doi.org/10.1016/j.neuroscience.2015.03.063
Fiacco TA, McCarthy KD (2018) Multiple lines of evidence indicate that gliotransmission does not occur under physiological conditions. J Neurosci 38(1):3–13. https://doi.org/10.1523/jneurosci.0016-17.2017
Savtchouk I, Volterra A (2018) Gliotransmission: beyond black-and-white. J Neurosci 38(1):14–25. https://doi.org/10.1523/jneurosci.0017-17.2017
Scofield MD (2017) Exploring the role of astroglial glutamate release and association with synapses in neuronal function and behavior. Biol Psychiatry. https://doi.org/10.1016/j.biopsych.2017.10.029
Bezzi P, Gundersen V, Galbete JL, Seifert G, Steinhäuser C, Pilati E, Volterra A (2004) Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci 7(6):613–620
Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747
Martineau M, Shi T, Puyal J, Knolhoff AM, Dulong J, Gasnier B, Klingauf J, Sweedler JV, Jahn R, Mothet JP (2013) Storage and uptake of d-serine into astrocytic synaptic-like vesicles specify gliotransmission. J Neurosci 33(8):3413–3423. https://doi.org/10.1523/jneurosci.3497-12.2013
Bohmbach K, Schwarz MK, Schoch S, Henneberger C (2018) The structural and functional evidence for vesicular release from astrocytes in situ. Brain Res Bull 136:65–75. https://doi.org/10.1016/j.brainresbull.2017.01.015
Hamilton NB, Attwell D (2010) Do astrocytes really exocytose neurotransmitters? Nat Rev Neurosci 11(4):227–238. https://doi.org/10.1038/nrn2803
Ye ZC, Wyeth MS, Baltan-Tekkok S, Ransom BR (2003) Functional hemichannels in astrocytes: a novel mechanism of glutamate release. J Neurosci 23(9):3588–3596
Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC, Nedergaard M (1998) Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci USA 95(26):15735–15740
Warr O, Takahashi M, Attwell D (1999) Modulation of extracellular glutamate concentration in rat brain slices by cystine-glutamate exchange. J Physiol 514(Pt 3):783–793. https://doi.org/10.1111/j.1469-7793.1999.783ad.x
Soria FN, Pérez-Samartín A, Martin A, Gona KB, Llop J, Szczupak B, Chara JC, Matute C, Domercq M (2014) Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage J Clin Invest. 124(8):3645–3655. https://doi.org/10.1172/jci71886
Duan S, Anderson CM, Keung EC, Chen Y, Chen Y, Swanson RA (2003) P2X7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci 23(4):1320–1328
Rosenberg PA, Knowles R, Knowles KP, Li Y (1994) Beta-adrenergic receptor-mediated regulation of extracellular adenosine in cerebral cortex in culture. J Neurosci 14(5 Pt 2):2953–2965
Wang CM, Chang YY, Kuo JS, Sun SH (2002) Activation of P2X(7) receptors induced [(3)H]GABA release from the RBA-2 type-2 astrocyte cell line through a Cl(−)/HCO(3)(−)-dependent mechanism. Glia 37:8–18. https://doi.org/10.1002/glia.10004
Park H, Han KS, Oh SJ, Jo S, Woo J, Yoon BE, Lee CJ (2013) High glutamate permeability and distal localization of Best1 channel in CA1 hippocampal astrocyte. Mol Brain 6:54. https://doi.org/10.1186/1756-6606-6-54
Han KS, Woo J, Park H, Yoon BJ, Choi S, Lee CJ (2013) Channel-mediated astrocytic glutamate release via Bestrophin-1 targets synaptic NMDARs. Mol Brain 6:4. https://doi.org/10.1186/1756-6606-6-4
Rose CR, Felix L, Zeug A, Dietrich D, Reiner A, Henneberger C (2018) Astroglial glutamate signaling and uptake in the hippocampus. Front Mol Neurosci 10:451. https://doi.org/10.3389/fnmol.2017.00451
Vandenberg RJ, Ryan RM (2013) Mechanisms of glutamate transport. Physiol Rev 93(4):1621–1657. https://doi.org/10.1152/physrev.00007.2013
Szatkowski M, Barbour B, Attwell D (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 348(6300):443–446
Tremblay MÈ, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci 31(45):16064–16069
Hayashi Y, Koyanagi S, Kusunose N, Okada R, Wu Z, Tozaki-Saitoh H, Ukai K, Kohsaka S, Inoue K, Ohdo S, Nakanishi H (2013) The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S. Sci Rep 3:2744. https://doi.org/10.1038/srep02744
Jewett KA, Krueger JM (2012) Humoral sleep regulation; interleukin-1 and tumor necrosis factor. Vitam Horm 89:241–257
Fonken LK, Kitt MM, Gaudet AD, Barrientos RM, Watkins LR, Maier SF (2016) Diminished circadian rhythms in hippocampal microglia may contribute to age-related neuroinflammatory sensitization. Neurobiol Aging 47:102–112
Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, Weeber EJ, Bickford PC, Gemma C (2011) CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci 31(45):16241–16250. https://doi.org/10.1523/jneurosci.3667-11.2011
Schafer DP, Lehrman EK, Stevens B (2013) The “quad-partite” synapse: microglia-synapse interactions in the developing and mature CNS. Glia 61(1):24–36. https://doi.org/10.1002/glia.22389
Gundersen V, Storm-Mathisen J, Bergersen LH (2015) Neuroglial transmission. Physiol Rev 95(3):695–726. https://doi.org/10.1152/physrev.00024.2014
McMullan SM, Phanavanh B, Li GG, Barger SW (2012) Metabotropic glutamate receptors inhibit microglial glutamate release. ASN Neuro. https://doi.org/10.1042/an20120044
Thomas AG, O’Driscoll CM, Bressler J, Kaufmann W, Rojas CJ, Slusher BS (2014) Small molecule glutaminase inhibitors block glutamate release from stimulated microglia. Biochem Biophys Res Commun 443(1):32–36. https://doi.org/10.1016/j.bbrc.2013.11.043
Noda M, Nakanishi H, Nabekura J, Akaike N (2000) AMPA-kainate subtypes of glutamate receptor in rat cerebral microglia. J Neurosci 20(1):251–258
Maezawa I, Jin LW (2010) Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J Neurosci 30(15):5346–5356. https://doi.org/10.1523/jneurosci.5966-09.2010
Huang Y, Zhao L, Jia B, Wu L, Li Y, Curthoys N, Zheng JC (2011) Glutaminase dysregulation in HIV-1-infected human microglia mediates neurotoxicity: relevant to HIV-1-associated neurocognitive disorders. J Neurosci 31(42):15195–15204. https://doi.org/10.1523/jneurosci.2051-11.2011
Erdmann N, Tian C, Huang Y, Zhao J, Herek S, Curthoys N, Zheng J (2009) In vitro glutaminase regulation and mechanisms of glutamate generation in HIV-1-infected macrophage. J Neurochem 109(2):551–561. https://doi.org/10.1111/j.1471-4159.2009.05989.x
Brown GC, Vilalta A (2015) How microglia kill neurons. Brain Res. 1628(Pt B):288–297. https://doi.org/10.1016/j.brainres.2015.08.031
Schlichter LC, Mertens T, Liu B (2011) Swelling activated Cl-channels in microglia: biophysics, pharmacology and role in glutamate release. Channels (Austin) 5(2):128–137
Bagayogo IP, Dreyfus CF (2009) Regulated release of BDNF by cortical oligodendrocytes is mediated through metabotropic glutamate receptors and the PLC pathway. ASN Neuro. https://doi.org/10.1042/an20090006
Frühbeis C, Fröhlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, Kirchhoff F, Möbius W, Goebbels S, Nave KA, Schneider A, Simons M, Klugmann M, Trotter J, Krämer-Albers EM (2013) Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11(7):e1001604. https://doi.org/10.1371/journal.pbio.1001604
Kessler JP (2013) Control of cleft glutamate concentration and glutamate spill-out by perisynaptic glia: uptake and diffusion barriers. PLoS One 8(8):e70791. https://doi.org/10.1371/journal.pone.0070791
van der Zeyden M, Oldenziel WH, Rea K, Cremers TI, Westerink BH (2008) Microdialysis of GABA and glutamate: analysis, interpretation and comparison with microsensors. Pharmacol Biochem Behav 90(2):135–147
Moghaddam B (1993) Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem 60(5):1650–1657
Dash MB, Douglas CL, Vyazovskiy VV, Cirelli C, Tononi G (2009) Long-term homeostasis of extracellular glutamate in the rat cerebral cortex across sleep and waking states. J Neurosci 29(3):620–629. https://doi.org/10.1523/jneurosci.5486-08.2009
Oldenziel WH, van der Zeyden M, Dijkstra G, Ghijsen WE, Karst H, Cremers TI, Westerink BH (2007) Monitoring extracellular glutamate in hippocampal slices with a microsensor. J Neurosci Methods 160(1):37–44
Kulagina NV, Shankar L, Michael AC (1999) Monitoring glutamate and ascorbate in the extracellular space of brain tissue with electrochemical microsensors. Anal Chem 71(22):5093–5100
Rahman MA, Kwon NH, Won MS, Choe ES, Shim YB (2005) Functionalized conducting polymer as an enzyme-immobilizing substrate: an amperometric glutamate microbiosensor for in vivo measurements. Anal Chem 77(15):4854–4860
Qin S, Van der Zeyden M, Oldenziel WH, Cremers TI, Westerink BH (2008) Microsensors for in vivo measurement of glutamate in brain tissue. Sensors (Basel) 8(11):6860–6884
Hascup KN, Hascup ER, Pomerleau F, Huettl P, Gerhardt GA (2008) Second-by-second measures of L-glutamate in the prefrontal cortex and striatum of freely moving mice. J Pharmacol Exp Ther 324(2):725–731
Hascup ER, Hascup KN, Stephens M, Pomerleau F, Huettl P, Gratton A, Gerhardt GA (2010) Rapid microelectrode measurements and the origin and regulation of extracellular glutamate in rat prefrontal cortex. J Neurochem. 115(6):1608–1620. https://doi.org/10.1111/j.1471-4159.2010.07066.x
Rutherford EC, Pomerleau F, Huettl P, Strömberg I, Gerhardt GA (2007) Chronic second-by-second measures of l-glutamate in the central nervous system of freely moving rats. J Neurochem 102(3):712–722
Cellar NA, Burns ST, Meiners JC, Chen H, Kennedy RT (2005) Microfluidic chip for low-flow push-pull perfusion sampling in vivo with on-line analysis of amino acids. Anal Chem 77(21):7067–7073
Boatell ML, Bendahan G, Mahy N (1995) Time-related cortical amino acid changes after basal forebrain lesion: a microdialysis study. J Neurochem 64(1):285–291
Lerma J, Herranz AS, Herreras O, Abraira V, Martín del Río R (1986) In vivo determination of extracellular concentration of amino acids in the rat hippocampus. A method based on brain dialysis and computerized analysis. Brain Res 384(1):145–155
Rosenberg PA, Amin S, Leitner M (1992) Glutamate uptake disguises neurotoxic potency of glutamate agonists in cerebral cortex in dissociated cell culture. J Neurosci 12(1):56–61
Celio MR, Spreafico R, De Biasi S, Vitellaro-Zuccarello L (1998) Perineuronal nets: past and present. Trends Neurosci 21(12):510–515
Syková E (2004) Extrasynaptic volume transmission and diffusion parameters of the extracellular space. Neuroscience 129(4):861–876
Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M (2013) Sleep drives metabolite clearance from the adult brain. Science 342(6156):373–377
Frischknecht R, Heine M, Perrais D, Seidenbecher CI, Choquet D, Gundelfinger ED (2009) Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci 12(7):897–904
Groc L, Choquet D, Stephenson FA, Verrier D, Manzoni OJ, Chavis P (2007) NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin. J Neurosci 27(38):10165–10175
Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14(6):383–400. https://doi.org/10.1038/nrn3504
Petralia RS (2012) Distribution of extrasynaptic NMDA receptors on neurons. Sci World J 2012:267120. https://doi.org/10.1100/2012/267120
Dore K, Stein IS, Brock JA, Castillo PE, Zito K, Sjöström PJ (2017) Unconventional NMDA receptor signaling. J Neurosci 37(45):10800–10807. https://doi.org/10.1523/jneurosci.1825-17.2017
Stroebel D, Casado M, Paoletti P (2018) Triheteromeric NMDA receptors: from structure to synaptic physiology. Curr Opin Physiol 02:1–12. https://doi.org/10.1016/j.cophys.2017.12.004
Tovar KR, Westbrook GL (2002) Mobile NMDA receptors at hippocampal synapses. Neuron 34(2):255–264
Lau CG, Zukin RS (2007) NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8(6):413–426
Harris AZ, Pettit DL (2007) Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices. J Physiol 584(Pt 2):509–519
Verkhratsky A, Kirchhoff F (2007) NMDA receptors in glia. Neuroscientist 13(1):28–37
Dzamba D, Honsa P, Valny M, Kriska J, Valihrach L, Novosadova V, Kubista M, Anderova M (2015) Quantitative analysis of glutamate receptors in glial cells from the cortex of GFAP/EGFP mice following ischemic injury: focus on NMDA receptors. Cell Mol Neurobiol 35(8):1187–1202
Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A (2006) NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J Neurosci 26(10):2673–2683
Murugan M, Sivakumar V, Lu J, Ling EA, Kaur C (2011) Expression of N-methyl d-aspartate receptor subunits in amoeboid microglia mediates production of nitric oxide via NF-κB signaling pathway and oligodendrocyte cell death in hypoxic postnatal rats. Glia 59(4):521–539
Kaindl AM, Degos V, Peineau S, Gouadon E, Chhor V, Loron G, Le Charpentier T, Josserand J, Ali C, Vivien D, Collingridge GL, Lombet A, Issa L, Rene F, Loeffler JP, Kavelaars A, Verney C, Mantz J, Gressens P (2012) Activation of microglial N-methyl-d-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. Ann Neurol 72(4):536–549
Singh P, Doshi S, Spaethling JM, Hockenberry AJ, Patel TP, Geddes-Klein DM, Lynch DR, Meaney DF (2012) N-methyl-d-aspartate receptor mechanosensitivity is governed by C terminus of NR2B subunit. J Biol Chem 287(6):4348–4359. https://doi.org/10.1074/jbc.m111.253740
Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W (2006) The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta 1762(11–12):1068–1082
Matott MP, Kline DD, Hasser EM (2017) Glial EAAT2 regulation of extracellular nTS glutamate critically controls neuronal activity and cardiorespiratory reflexes. J Physiol 595(17):6045–6063. https://doi.org/10.1113/jp274620
Kopach O, Voitenko N (2013) Extrasynaptic AMPA receptors in the dorsal horn: evidence and functional significance. Brain Res Bull 93:47–56. https://doi.org/10.1016/j.brainresbull.2012.11.004
Nusser Z (2000) AMPA and NMDA receptors: similarities and differences in their synaptic distribution. Curr Opin Neurobiol 10(3):337–341
Borgdorff AJ, Choquet D (2002) Regulation of AMPA receptor lateral movements. Nature 417(6889):649–653
Höft S, Griemsmann S, Seifert G, Steinhäuser C (2014) Heterogeneity in expression of functional ionotropic glutamate and GABA receptors in astrocytes across brain regions: insights from the thalamus. Philos Trans R Soc Lond B Biol Sci 369(1654):20130602
Seifert G, Steinhäuser C (1995) Glial cells in the mouse hippocampus express AMPA receptors with an intermediate Ca2 + permeability. Eur J Neurosci 7(9):1872–1881
Fan D, Grooms SY, Araneda RC, Johnson AB, Dobrenis K, Kessler JA, Zukin RS (1999) AMPA receptor protein expression and function in astrocytes cultured from hippocampus. J Neurosci Res 57(4):557–571
Zhou M, Kimelberg HK (2001) Freshly isolated hippocampal CA1 astrocytes comprise two populations differing in glutamate transporter and AMPA receptor expression. J Neurosci 21(20):7901–7908
Cervetto C, Frattaroli D, Venturini A, Passalacqua M, Nobile M, Alloisio S, Tacchetti C, Maura G, Agnati LF, Marcoli M (2015) Calcium-permeable AMPA receptors trigger vesicular glutamate release from Bergmann gliosomes. Neuropharmacology 99:396–407. https://doi.org/10.1016/j.neuropharm.2015.08.011
Saab AS, Neumeyer A, Jahn HM, Cupido A, Šimek AA, Boele HJ, Scheller A, Le Meur K, Götz M, Monyer H, Sprengel R, Rubio ME, Deitmer JW, De Zeeuw CI, Kirchhoff F (2012) Bergmann glial AMPA receptors are required for fine motor coordination. Science 337(6095):749–753. https://doi.org/10.1126/science.1221140
Beppu K, Kosai Y, Kido MA, Akimoto N, Mori Y, Kojima Y, Fujita K, Okuno Y, Yamakawa Y, Ifuku M, Shinagawa R, Nabekura J, Sprengel R, Noda M (2013) Expression, subunit composition, and function of AMPA-type glutamate receptors are changed in activated microglia; possible contribution of GluA2 (GluR-B)-deficiency under pathological conditions. Glia 61(6):881–891. https://doi.org/10.1002/glia.22481
Noda M, Nakanishi H, Nabekura J, Akaike N (2000) AMPA-kainate subtypes of glutamate receptor in rat cerebral microglia. J Neurosci 20(1):251–258
Ferraguti F, Shigemoto R (2006) Metabotropic glutamate receptors. Cell Tissue Res 326(2):483–504
Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60(7–8):1017–1041. https://doi.org/10.1016/j.neuropharm.2010.10.022
Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237
Baude A, Nusser Z, Roberts JD, Mulvihill E, McIlhinney RA, Somogyi P (1993) The metabotropic glutamate receptor (mGluR1 alpha) is concentrated at perisynaptic membrane of neuronal subpopulations as detected by immunogold reaction. Neuron 11(4):771–787
Nusser Z, Mulvihill E, Streit P, Somogyi P (1994) Subsynaptic segregation of metabotropic and ionotropic glutamate receptors as revealed by immunogold localization. Neuroscience 61(3):421–427
Tu JC, Xiao B, Naisbitt S, Yuan JP, Petralia RS, Brakeman P, Doan A, Aakalu VK, Lanahan AA, Sheng M, Worley PF (1999) Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23(3):583–592
Ferraguti F, Crepaldi L, Nicoletti F (2008) Metabotropic glutamate 1 receptor: current concepts and perspectives. Pharmacol Rev 60(4):536–581. https://doi.org/10.1124/pr.108.000166
Luján R, Roberts JD, Shigemoto R, Ohishi H, Somogyi P (1997) Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1 alpha, mGluR2 and mGluR5, relative to neurotransmitter release sites. J Chem Neuroanat 13(4):219–241
Tamaru Y, Nomura S, Mizuno N, Shigemoto R (2001) Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience 106(3):481–503
Aronica E, Gorter JA, Ijlst-Keizers H, Rozemuller AJ, Yankaya B, Leenstra S, Troost D (2003) Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins. Eur J Neurosci 17(10):2106–2118
Petralia RS, Wang YX, Niedzielski AS, Wenthold RJ (1996) The metabotropic glutamate receptors, mGluR2 and mGluR3, show unique postsynaptic, presynaptic and glial localizations. Neuroscience 71(4):949–976
Sun W, McConnell E, Pare JF, Xu Q, Chen M, Peng W, Lovatt D, Han X, Smith Y, Nedergaard M (2013) Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science 339(6116):197–200. https://doi.org/10.1126/science.1226740
Nizar K, Uhlirova H, Tian P, Saisan PA, Cheng Q, Reznichenko L, Weldy KL, Steed TC, Sridhar VB, MacDonald CL, Cui J, Gratiy SL, Sakadzić S, Boas DA, Beka TI, Einevoll GT, Chen J, Masliah E, Dale AM, Silva GA, Devor A (2013) In vivo stimulus-induced vasodilation occurs without IP3 receptor activation and may precede astrocytic calcium increase. J Neurosci 33(19):8411–8422. https://doi.org/10.1523/jneurosci.3285-12.2013
Kim SK, Nabekura J, Koizumi S (2017) Astrocyte-mediated synapse remodeling in the pathological brain. Glia 65(11):1719–1727. https://doi.org/10.1002/glia.23169
Farso MC, O’Shea RD, Beart PM (2009) Evidence group I mGluR drugs modulate the activation profile of lipopolysaccharide-exposed microglia in culture. Neurochem Res 34(10):1721–1728. https://doi.org/10.1007/s11064-009-9999-3
Piers TM, Heales SJ, Pocock JM (2011) Positive allosteric modulation of metabotropic glutamate receptor 5 down-regulates fibrinogen-activated microglia providing neuronal protection. Neurosci Lett 505(2):140–145. https://doi.org/10.1016/j.neulet.2011.10.007
Kim YK, Na KS (2016) Role of glutamate receptors and glial cells in the pathophysiology of treatment-resistant depression. Prog Neuropsychopharmacol Biol Psychiatry 70:117–126. https://doi.org/10.1016/j.pnpbp.2016.03.009
Kaushal V, Schlichter LC (2008) Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J Neurosci 28(9):2221–2230. https://doi.org/10.1523/jneurosci.5643-07.2008
Rose CF, Verkhratsky A, Parpura V (2013) Astrocyte glutamine synthetase: pivotal in health and disease. Biochem Soc Trans 41(6):1518–1524. https://doi.org/10.1042/bst20130237
Trabelsi Y, Amri M, Becq H, Molinari F, Aniksztejn L (2017) The conversion of glutamate by glutamine synthase in neocortical astrocytes from juvenile rat is important to limit glutamate spillover and peri/extrasynaptic activation of NMDA receptors. Glia 65(2):401–415. https://doi.org/10.1002/glia.23099
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1–105
Vandenberg RJ, Ryan RM (2013) Mechanisms of glutamate transport. Physiol Rev 93(4):1621–1657. https://doi.org/10.1152/physrev.00007.2013
Milton M, Smith PD (2018) It’s all about timing: the involvement of Kir4.1 channel regulation in acute ischemic stroke pathology. Front Cell Neurosci 12:36. https://doi.org/10.3389/fncel.2018.00036
Wadiche JI, Amara SG, Kavanaugh MP (1995) Ion fluxes associated with excitatory amino acid transport. Neuron 15(3):721–728
Fairman WA, Vandenberg RJ, Arriza JL, Kavanaugh MP, Amara SG (1995) An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375(6532):599–603
Haugeto O, Ullensvang K, Levy LM, Chaudhry FA, Honoré T, Nielsen M, Lehre KP, Danbolt NC (1996) Brain glutamate transporter proteins form homomultimers. J Biol Chem. 271(44):27715–27722
Lehre KP, Danbolt NC (1998) The number of glutamate transporter subtype molecules at glutamatergic synapses: chemical and stereological quantification in young adult rat brain. J Neurosci 18(21):8751–8757
Furness DN, Dehnes Y, Akhtar AQ, Rossi DJ, Hamann M, Grutle NJ, Gundersen V, Holmseth S, Lehre KP, Ullensvang K, Wojewodzic M, Zhou Y, Attwell D, Danbolt NC (2008) A quantitative assessment of glutamate uptake into hippocampal synaptic terminals and astrocytes: new insights into a neuronal role for excitatory amino acid transporter 2 (EAAT2). Neuroscience 157(1):80–94. https://doi.org/10.1016/j.neuroscience.2008.08.043
Holmseth S, Dehnes Y, Huang YH, Follin-Arbelet VV, Grutle NJ, Mylonakou MN, Plachez C, Zhou Y, Furness DN, Bergles DE, Lehre KP, Danbolt NC (2012) The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the mammalian CNS. J Neurosci 32(17):6000–6013. https://doi.org/10.1523/jneurosci.5347-11.2012
Dehnes Y, Chaudhry FA, Ullensvang K, Lehre KP, Storm-Mathisen J, Danbolt NC (1998) The glutamate transporter EAAT4 in rat cerebellar Purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J Neurosci 18(10):3606–3619
Arriza JL, Eliasof S, Kavanaugh MP, Amara SG (1997) Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Acad Sci USA. 94(8):4155–4160
Danbolt NC, Furness DN, Zhou Y (2016) Neuronal vs glial glutamate uptake: resolving the conundrum. Neurochem Int. 98:29–45. https://doi.org/10.1016/j.neuint.2016.05.009
Pál B (2015) Astrocytic actions on extrasynaptic neuronal currents. Front Cell Neurosci 9:474. https://doi.org/10.3389/fncel.2015.00474
Arnth-Jensen N, Jabaudon D, Scanziani M (2002) Cooperation between independent hippocampal synapses is controlled by glutamate uptake. Nat Neurosci 5(4):325–331
Lozovaya NA, Grebenyuk SE, Tsintsadze TSh, Feng B, Monaghan DT, Krishtal OA (2004) Extrasynaptic NR2B and NR2D subunits of NMDA receptors shape ‘superslow’ afterburst EPSC in rat hippocampus. J Physiol 558(Pt 2):451–463
Marcaggi P, Billups D, Attwell D (2003) The role of glial glutamate transporters in maintaining the independent operation of juvenile mouse cerebellar parallel fibre synapses. J Physiol 552(Pt 1):89–107
Gómez-Gonzalo M, Martin-Fernandez M, Martínez-Murillo R, Mederos S, Hernández-Vivanco A, Jamison S, Fernandez AP, Serrano J, Calero P, Futch HS, Corpas R, Sanfeliu C, Perea G, Araque A (2017) Neuron-astrocyte signaling is preserved in the aging brain. Glia 65(4):569–580. https://doi.org/10.1002/glia.23112
Kovács A, Pál B (2017) Astrocyte-dependent slow inward currents (SICs) participate in neuromodulatory mechanisms in the pedunculopontine nucleus (PPN). Front Cell Neurosci 11:16. https://doi.org/10.3389/fncel.2017.00016
Pirttimaki TM, Sims RE, Saunders G, Antonio SA, Codadu NK, Parri HR (2017) Astrocyte-mediated neuronal synchronization properties revealed by false gliotransmitter release. J Neurosci 37(41):9859–9870. https://doi.org/10.1523/jneurosci.2761-16.2017
Wu DC, Chen RY, Cheng TC, Chiang YC, Shen ML, Hsu LL, Zhou N (2017) Spreadingdepression promotes astrocytic calcium oscillations and enhances gliotransmission to hippocampal neurons. Cereb Cortex 1:1–13. https://doi.org/10.1093/cercor/bhx192
Kovács A, Bordás C, Bíró T, Hegyi Z, Antal M, Szücs P, Pál B (2017) Direct presynaptic and indirect astrocyte-mediated mechanisms both contribute to endocannabinoid signaling in the pedunculopontine nucleus of mice. Brain Struct Funct 222(1):247–266. https://doi.org/10.1007/s00429-016-1214-0
Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, Dziewczapolski G, Nakamura T, Cao G, Pratt AE, Kang YJ, Tu S, Molokanova E, McKercher SR, Hires SA, Sason H, Stouffer DG, Buczynski MW, Solomon JP, Michael S, Powers ET, Kelly JW, Roberts A, Tong G, Fang-Newmeyer T, Parker J, Holland EA, Zhang D, Nakanishi N, Chen HS, Wolosker H, Wang Y, Parsons LH, Ambasudhan R, Masliah E, Heinemann SF, Piña-Crespo JC, Lipton SA (2013) Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci USA 110(27):E2518–E2527. https://doi.org/10.1073/pnas.1306832110
Chanda S, Xu-Friedman MA (2011) Excitatory modulation in the cochlear nucleus through group I metabotropic glutamate receptor activation. J Neurosci 31(20):7450–7455. https://doi.org/10.1523/jneurosci.1193-11.2011
Yang Y, Xu-Friedman MA (2015) Different pools of glutamate receptors mediate sensitivity to ambient glutamate in the cochlear nucleus. J Neurophysiol 113(10):3634–3645. https://doi.org/10.1152/jn.00693.2014
Pai YH, Lim CS, Park KA, Cho HS, Lee GS, Shin YS, Kim HW, Jeon BH, Yoon SH, Park JB (2016) Facilitation of AMPA receptor-mediated steady-state current by extrasynaptic NMDA receptors in supraoptic magnocellular neurosecretory cells. Korean J Physiol Pharmacol 20(4):425–432. https://doi.org/10.4196/kjpp.2016.20.4.425
Stern JE, Son S, Biancardi VC, Zheng H, Sharma N, Patel KP (2016) Astrocytes contribute to angiotensin II stimulation of hypothalamic neuronal activity and sympathetic outflow. Hypertension 68(6):1483–1493
Zhang M, Biancardi VC, Stern JE (2017) An increased extrasynaptic NMDA tone inhibits A-type K + current and increases excitability of hypothalamic neurosecretory neurons in hypertensive rats. J Physiol 595(14):4647–4661. https://doi.org/10.1113/jp274327
Sasaki T, Beppu K, Tanaka KF, Fukazawa Y, Shigemoto R, Matsui K (2012) Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation. Proc Natl Acad Sci USA 109:20720–20725. https://doi.org/10.1073/pnas.1213458109
Libri V, Constanti A, Zibetti M, Postlethwaite M (1997) Metabotropic glutamate receptor subtypes mediating slow inward tail current (IADP) induction and inhibition of synaptic transmission in olfactory cortical neurones. Br J Pharmacol 120(6):1083–1095
Partridge JG, Lewin AE, Yasko JR, Vicini S (2014) Contrasting actions of group I metabotropic glutamate receptors in distinct mouse striatal neurones. J Physiol 592(13):2721–2733. https://doi.org/10.1113/jphysiol.2014.272773
Zhang Z, Séguéla P (2010) Metabotropic induction of persistent activity in layers II/III of anterior cingulate cortex. Cereb Cortex 20(12):2948–2957. https://doi.org/10.1093/cercor/bhq043
Jian K, Cifelli P, Pignatelli A, Frigato E, Belluzzi O (2010) Metabotropic glutamate receptors 1 and 5 differentially regulate bulbar dopaminergic cell function. Brain Res 1354:47–63. https://doi.org/10.1016/j.brainres.2010.07.104
Mannaioni G, Marino MJ, Valenti O, Traynelis SF, Conn PJ (2001) Metabotropic glutamate receptors 1 and 5 differentially regulate CA1 pyramidal cell function. J Neurosci 21(16):5925–5934
Ster J, Mateos JM, Grewe BF, Coiret G, Corti C, Corsi M, Helmchen F, Gerber U (2011) Enhancement of CA3 hippocampal network activity by activation of group II metabotropic glutamate receptors. Proc Natl Acad Sci USA 108(24):9993–9997. https://doi.org/10.1073/pnas.1100548108
Kõszeghy Á, Kovács A, Bíró T, Szücs P, Vincze J, Hegyi Z, Antal M, Pál B (2015) Endocannabinoid signaling modulates neurons of the pedunculopontine nucleus (PPN) via astrocytes. Brain Struct Funct 220:3023–3041. https://doi.org/10.1007/s00429-014-0842-5
Kohlmeier KA, Christensen MH, Kristensen MP, Kristiansen U (2013) Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons. Neuropharmacology 66:99–113. https://doi.org/10.1016/j.neuropharm.2012.02.016
Irie T, Fukui I, Ohmori H (2006) Activation of GIRK channels by muscarinic receptors and group II metabotropic glutamate receptors suppresses Golgi cell activity in the cochlear nucleus of mice. J Neurophysiol 96(5):2633–2644
Hermes ML, Renaud LP (2011) Postsynaptic and presynaptic group II metabotropic glutamate receptor activation reduces neuronal excitability in rat midline paraventricular thalamic nucleus. J Pharmacol Exp Ther 336(3):840–849. https://doi.org/10.1124/jpet.110.176149
Polsky A, Mel BW, Schiller J (2004) Computational subunits in thin dendrites of pyramidal cells. Nat Neurosci 7(6):621–627
Polsky A, Mel B, Schiller J (2009) Encoding and decoding bursts by NMDA spikes in basal dendrites of layer 5 pyramidal neurons. J Neurosci 29(38):11891–11903. https://doi.org/10.1523/jneurosci.5250-08.2009
Oikonomou KD, Short SM, Rich MT, Antic SD (2012) Extrasynaptic glutamate receptor activation as cellular bases for dynamic range compression in pyramidal neurons. Front Physiol 3:334. https://doi.org/10.3389/fphys.2012.00334
Milojkovic BA, Radojicic MS, Goldman-Rakic PS, Antic SD (2004) Burst generation in rat pyramidal neurones by regenerative potentials elicited in a restricted part of the basilar dendritic tree. J Physiol 558(Pt 1):193–211
Milojkovic BA, Wuskell JP, Loew LM, Antic SD (2005) Initiation of sodium spikelets in basal dendrites of neocortical pyramidal neurons. J Membr Biol 208(2):155–169
Monaghan DT, Jane DE (2009) Pharmacology of NMDA receptors in biology of the NMDA receptor. Van Dongen AM (ed), Frontiers in Neuroscience. CRC Press, Boca Raton
Liu DD, Yang Q, Li ST (2013) Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons. Brain Res Bull 93:10–16. https://doi.org/10.1016/j.brainresbull.2012.12.003
Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T (1998) dl-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters. Mol Pharmacol 53(2):195–201
Bridges RJ, Esslinger CS (2005) The excitatory amino acid transporters: pharmacological insights on substrate and inhibitorspecificity of the EAAT subtypes. Pharmacol Ther 107(3):271–285
Bunch L, Erichsen MN, Jensen AA (2009) Excitatory amino acid transporters as potential drug targets. Expert Opin Ther Targets 13(6):719–731. https://doi.org/10.1517/14728220902926127
Kiryk A, Aida T, Tanaka K, Banerjee P, Wilczynski GM, Meyza K, Knapska E, Filipkowski RK, Kaczmarek L, Danysz W (2008) Behavioral characterization of GLT1 (±) mice as a model of mild glutamatergic hyperfunction. Neurotox Res 13(1):19–30
Petr GT, Sun Y, Frederick NM, Zhou Y, Dhamne SC, Hameed MQ, Miranda C, Bedoya EA, Fischer KD, Armsen W, Wang J, Danbolt NC, Rotenberg A, Aoki CJ, Rosenberg PA (2005) Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation. J Neurosci 25(29):6907–6910
Langer J, Gerkau NJ, Derouiche A, Kleinhans C, Moshrefi-Ravasdjani B, Fredrich M, Kafitz KW, Seifert G, Steinhäuser C, Rose CR (2017) Rapid sodium signaling couples glutamate uptake to breakdown of ATP in perivascular astrocyte endfeet. Glia 65(2):293–308. https://doi.org/10.1002/glia.23092
Figueiredo M, Lane S, Tang F, Liu BH, Hewinson J, Marina N, Kasymov V, Souslova EA, Chudakov DM, Gourine AV, Teschemacher AG, Kasparov S (2011) Optogenetic experimentation on astrocytes. Exp Physiol 96(1):40–50
Bang J, Kim HY, Lee H (2016) Optogenetic and chemogenetic approaches for studying astrocytes and gliotransmitters. Exp Neurobiol 25(5):205–221
Cho WH, Barcelon E, Lee SJ (2016) Optogenetic glia manipulation: possibilities and future prospects. Exp Neurobiol 25(5):197–204
Beppu K, Sasaki T, Tanaka KF, Yamanaka A, Fukazawa Y, Shigemoto R, Matsui K (2014) Optogenetic countering of glial acidosis suppresses glial glutamate release and ischemic brain damage. Neuron 81(2):314–320. https://doi.org/10.1016/j.neuron.2013.11.011
Figueiredo M, Lane S, Stout RF Jr, Liu B, Parpura V, Teschemacher AG, Kasparov S (2014) Comparative analysis of optogenetic actuators in cultured astrocytes. Cell Calcium 56(3):208–214. https://doi.org/10.1016/j.ceca.2014.07.007
Pasti L, Zonta M, Pozzan T, Vicini S, Carmignoto G (2001) Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate. J Neurosci 21(2):477–484
Qin S, Van der Zeyden M, Oldenziel WH, Cremers TI, Westerink BH (2008) Microsensors for in vivo measurement of glutamate in brain tissue. Sensors (Basel) 8(11):6860–6884
Akagi Y, Hashigasako A, Degenaar P, Iwabuchi S, Hasan Q, Morita Y, Tamiya E (2003) Enzyme-linked sensitive fluorometric imaging of glutamate release from cerebral neurons of chick embryos. J Biochem 134(3):353–358
Marvin JS, Borghuis BG, Tian L, Cichon J, Harnett MT, Akerboom J, Gordus A, Renninger SL, Chen TW, Bargmann CI, Orger MB, Schreiter ER, Demb JB, Gan WB, Hires SA, Looger LL (2013) An optimized fluorescent probe for visualizing glutamate neurotransmission. Nat Methods 10(2):162–170. https://doi.org/10.1038/nmeth.2333
Wu J, Abdelfattah AS, Zhou H, Ruangkittisakul A, Qian Y, Ballanyi K, Campbell RE (2018) Geneticallyencoded glutamate indicators with altered color and topology. ACS Chem Biol. https://doi.org/10.1021/acschembio.7b01085
Namiki S, Sakamoto H, Iinuma S, Iino M, Hirose K (2007) Optical glutamate sensor for spatiotemporal analysis of synaptic transmission. Eur J Neurosci 25(8):2249–2259
Okubo Y, Sekiya H, Namiki S, Sakamoto H, Iinuma S, Yamasaki M, Watanabe M, Hirose K, Iino M (2010) Imaging extrasynaptic glutamate dynamics in the brain. Proc Natl Acad Sci USA 107(14):6526–6531
Okumoto S, Looger LL, Micheva KD, Reimer RJ, Smith SJ, Frommer WB (2005) Detection of glutamate release from neurons by genetically encoded surface-displayed FRET nanosensors. Proc Natl Acad Sci USA 102(24):8740–8745
Hires SA, Zhu Y, Tsien RY (2008) Optical measurement of synaptic glutamate spillover and reuptake by linker optimized glutamate-sensitive fluorescent reporters. Proc Natl Acad Sci USA 105(11):4411–4416
Kimelberg HK, Goderie SK, Higman S, Pang S, Waniewski RA (1990) Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J Neurosci 10(5):1583–1591
Kozlov AS, Angulo MC, Audinat E, Charpak S (2006) Target cell-specific modulation of neuronal activity by astrocytes. Proc Natl Acad Sci USA 103:10058–10063. https://doi.org/10.1073/pnas.0603741103
Le Meur K, Galante M, Angulo MC, Audinat E (2007) Tonic activation of NMDA receptors by ambient glutamate of non-synaptic origin in the rat hippocampus. J Physiol 580(Pt 2):373–383. https://doi.org/10.1113/jphysiol.2006.123570
Jiménez-González C, Pirttimaki T, Cope DW, Parri HR (2011) Non-neuronal, slow GABA signalling in the ventrobasal thalamus targets δ-subunit-containing GABAA receptors. Eur J Neurosci 33:1471–1482. https://doi.org/10.1111/j.1460-9568.2011.07645.x
Pirttimaki T, Parri HR, Crunelli V (2013) Astrocytic GABA transporter GAT-1 dysfunction in experimental absence seizures. J Physiol 591:823–833. https://doi.org/10.1113/jphysiol.2012.242016
Moráles I, Fuentes A, Gonzalez-Hernandez T, Rodríguez M (2009) Osmosensitive response of glutamate in the substantia nigra. Exp Neurol 220(2):335–340. https://doi.org/10.1016/j.expneurol.2009.09.010
Santello M, Bezzi P, Volterra A (2011) TNFα controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69:988–1001. https://doi.org/10.1016/j.neuron.2011.02.003
Wang YF, Sun MY, Hou Q, Parpura V (2013) Hyposmolality differentially and spatiotemporally modulates levels of glutamine synthetase and serine racemase in rat supraoptic nucleus. Glia 61(4):529–538. https://doi.org/10.1002/glia.22453
Wang YF, Parpura V (2016) Central role of maladapted astrocytic plasticity in ischemic brain edema formation. Front Cell Neurosci 10:129. https://doi.org/10.3389/fncel.2016.00129
Hertz L, Zielke HR (2004) Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci 27(12):735–743
Rebec GV, Wang Z (2001) Behavioral activation in rats requires endogenous ascorbate release in striatum. Journal of Neuroscience 21(2):668–675
Darby M, Kuzmiski JB, Panenka W, Feighan D, MacVicar BA (2003) ATP released from astrocytes during swelling activates chloride channels. J Neurophysiol 89(4):1870–1877
Mulligan SJ, MacVicar BA (2004) Calcium transients in astrocyte endfeet cause cerebrovascular constrictions. Nature 431(7005):195–199
Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G (2003) Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6(1):43–50
Girouard H, Bonev AD, Hannah RM, Meredith A, Aldrich RW, Nelson MT (2010) Astrocytic endfoot Ca2 + and BK channels determine both arteriolar dilation and constriction. Proc Natl Acad Sci USA. 107(8):3811–3816. https://doi.org/10.1073/pnas.0914722107
Wake H, Lee PR, Fields RD (2011) Control of local protein synthesis and initial events in myelination by action potentials. Science 333(6049):1647–1651. https://doi.org/10.1126/science.1206998
Lundgaard I, Luzhynskaya A, Stockley JH, Wang Z, Evans KA, Swire M, Volbracht K, Gautier HO, Franklin RJ, Ffrench-Constant Charles, Attwell D, Káradóttir RT (2013) Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes. PLoS Biol 11(12):e1001743. https://doi.org/10.1371/journal.pbio.1001743
Gallo V, Zhou JM, McBain CJ, Wright P, Knutson PL, Armstrong RC (1996) Oligodendrocyte progenitor cell proliferation and lineage progression are regulated by glutamate receptor-mediated K + channel block. J Neurosci 16(8):2659–2670
Yuan X, Eisen AM, McBain CJ, Gallo V (1998) A role for glutamate and its receptors in the regulation of oligodendrocyte development in cerebellar tissue slices. Development 125(15):2901–2914
Naskar K, Stern JE (2014) A functional coupling between extrasynaptic NMDA receptors and A-type K + channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity. J Physiol 592(13):2813–2827. https://doi.org/10.1113/jphysiol.2014.270793
Jiao R, Cui D, Wang SC, Li D, Wang YF (2017) Interactions of the mechanosensitive channels with extracellular matrix, integrins, and cytoskeletal network in osmosensation. Front Mol Neurosci 10:96. https://doi.org/10.3389/fnmol.2017.00096 (eCollection 2017)
Wang YF, Liu LX, Yang HP (2011) Neurophysiological involvement in hypervolemic hyponatremia-evoked by hypersecretion of vasopressin. Transl Biomed 2(2):3
Wang YF, Hatton GI (2009) Astrocytic plasticity and patterned oxytocin neuronal activity: dynamic interactions. J Neurosci 29(6):1743–1754. https://doi.org/10.1523/jneurosci.4669-08.2009
Wang P, Qin D, Wang YF (2017) Oxytocin rapidly changes astrocytic GFAP plasticity by differentially modulating the expressions of pERK 1/2 and protein kinase A. Front Mol Neurosci 10:262. https://doi.org/10.3389/fnmol.2017.00262
Shu Q, Zhang J, Ma W, Lei Y, Zhou D (2017) Orexin-A promotes Glu uptake by OX1R/PKCα/ERK1/2/GLT-1 pathway in astrocytes and protects co-cultured astrocytes and neurons against apoptosis in anoxia/hypoglycemic injury in vitro. Mol Cell Biochem 425(1–2):103–112. https://doi.org/10.1007/s11010-016-2866-z
Mark J, Godin Y, Mandel P (1969) Biosynthesis of aspartic, glutamic, gamma-aminobutyric acids and glutamine in brain of rats deprived of total sleep or paradoxical sleep. J Neurochem 16(8):1263–1272
Bettendorff L, Sallanon-Moulin M, Touret M, Wins P, Margineanu I, Schoffeniels E (1996) Paradoxical sleep deprivation increases the content of glutamate and glutamine in rat cerebral cortex. Sleep 19(1):65–71
Lopez-Rodriguez F, Medina-Ceja L, Wilson CL, Jhung D, Morales-Villagran A (2006) Changes in extracellular glutamate levels in rat orbitofrontal cortex during sleep and wakefulness. Arch Med Res 38(1):52–55
Azuma S, Kodama T, Honda K, Inoué S (1996) State-dependent changes of extracellular glutamate in the medial preoptic area in freely behaving rats. Neurosci Lett 214(2–3):179–182
Kékesi KA, Dobolyi A, Salfay O, Nyitrai G, Juhász G (1997) Slow wave sleep is accompanied by release of certain amino acids in the thalamus of cats. NeuroReport 8(5):1183–1186
Kodama T, Honda Y (1999) Acetylcholine and glutamate release during sleep-wakefulness in the pedunculopontine tegmental nucleus and norepinephrine changes regulated by nitric oxide. Psychiatry Clin Neurosci 53(2):109–111
Briggs C, Hirasawa M, Semba K (2018) Sleep deprivation distinctly alters glutamate transporter 1 apposition and excitatory transmission to orexin and MCH neurons. J Neurosci 38(10):2505–2518. https://doi.org/10.1523/jneurosci.2179-17.2018
Poskanzer KE, Yuste R (2016) Astrocytes regulate cortical state switching in vivo. Proc Natl Acad Sci USA 113(19):E2675–E2684. https://doi.org/10.1073/pnas.1520759113
Pelluru D, Konadhode RR, Bhat NR, Shiromani PJ (2016) Optogenetic stimulation of astrocytes in the posterior hypothalamus increases sleep at night in C57BL/6J mice. Eur J Neurosci 43(10):1298–1306. https://doi.org/10.1111/ejn.13074
Baskys A, Malenka RC (1991) Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus. J Physiol 444:687–701
Xi ZX, Baker DA, Shen H, Carson DS, Kalivas PW (2002) Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens. J Pharmacol Exp Ther 300(1):162–171
Cochilla AJ, Alford S (1998) Metabotropic glutamate receptor-mediated control of neurotransmitter release. Neuron 20(5):1007–1016
Hu G, Duffy P, Swanson C, Ghasemzadeh MB, Kalivas PW (1999) The regulation of dopamine transmission by metabotropic glutamate receptors. J Pharmacol Exp Ther 289(1):412–416
Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22(5):208–215
Papouin T, Dunphy J, Tolman M, Foley JC, Haydon PG (2017) Astrocytic control of synaptic function. Philos Trans R Soc Lond B Biol Sci. https://doi.org/10.1098/rstb.2016.0154
Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW (2002) The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 22(20):9134–9141
Perea G, Gómez R, Mederos S, Covelo A, Ballesteros JJ, Schlosser L, Hernández-Vivanco A, Martín-Fernández M, Quintana R, Rayan A, Díez A, Fuenzalida M, Agarwal A, Bergles DE, Bettler B, Manahan-Vaughan D, Martín ED, Kirchhoff F, Araque A (2016) Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks. Elife 5. https://doi.org/10.7554/elife.20362
Covelo A, Araque A (2018) Neuronal activity determines distinct gliotransmitter release from a single astrocyte. Elife 7. https://doi.org/10.7554/elife.32237
Wu YW, Grebenyuk S, McHugh TJ, Rusakov DA, Semyanov A (2012) Backpropagating action potentials enable detection of extrasynaptic glutamate by NMDA receptors. Cell Rep 1(5):495–505. https://doi.org/10.1016/j.celrep.2012.03.007
Turrigiano G (2012) Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harb Perspect Biol 4(1):a005736. https://doi.org/10.1101/cshperspect.a005736
Fernandes D, Carvalho AL (2016) Mechanisms of homeostatic plasticity in the excitatory synapse. J Neurochem 139(6):973–996. https://doi.org/10.1111/jnc.13687
Sims RE, Butcher JB, Parri HR, Glazewski S (2015) Astrocyte and neuronal plasticity in the somatosensory system. Neural Plast 2015:732014. https://doi.org/10.1155/2015/732014
Soares C, Lee KF, Nassrallah W, Béïque JC (2013) Differential subcellular targeting of glutamate receptor subtypes during homeostatic synaptic plasticity. J Neurosci 33(33):13547–13559. https://doi.org/10.1523/jneurosci.1873-13.2013
Liu L, Wong TP, Pozza MF, Lingenhoehl K, Wang Y, Sheng M, Auberson YP, Wang YT (2004) Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304(5673):1021–1024
Massey PV, Johnson BE, Moult PR, Auberson YP, Brown MW, Molnar E, Collingridge GL, Bashir ZI (2004) Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci 24(36):7821–7828
Toyoda H, Zhao MG, Zhuo M (2005) Roles of NMDA receptor NR2A and NR2B subtypes for long-term depression in the anterior cingulate cortex. Eur J Neurosci 22(2):485–494
Weitlauf C, Honse Y, Auberson YP, Mishina M, Lovinger DM, Winder DG (2005) Activation of NR2A-containing NMDA receptors is not obligatory for NMDA receptor-dependent long-term potentiation. J Neurosci 25(37):8386–8390
Berberich S, Punnakkal P, Jensen V, Pawlak V, Seeburg PH, Hvalby Ø, Köhr G (2005) Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation. J Neurosci 25(29):6907–6910
Morishita W, Lu W, Smith GB, Nicoll RA, Bear MF, Malenka RC (2007) Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression. Neuropharmacology 52(1):71–76
Kollen M, Dutar P, Jouvenceau A (2008) The magnitude of hippocampal long term depression depends on the synaptic location of activated NR2-containing N-methyl-d-aspartate receptors. Neuroscience 154(4):1308–1317. https://doi.org/10.1016/j.neuroscience.2008.04.045
Yang Q, Zhu G, Liu D, Ju JG, Liao ZH, Xiao YX, Zhang Y, Chao N, Wang J, Li W, Luo JH, Li ST (2017) Extrasynaptic NMDA receptor dependent long-term potentiation of hippocampal CA1 pyramidal neurons. Sci Rep 7(1):3045. https://doi.org/10.1038/s41598-017-03287-7
Papouin T, Ladépêche L, Ruel J, Sacchi S, Labasque M, Hanini M, Groc L, Pollegioni L, Mothet JP, Oliet SH (2012) Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 150(3):633–646. https://doi.org/10.1016/j.cell.2012.06.029
Sun W, McConnell E, Pare JF, Xu Q, Chen M, Peng W, Lovatt D, Han X, Smith Y, Nedergaard M (2013) Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Science. 339(6116):197–200. https://doi.org/10.1126/science.1226740
Latour A, Grintal B, Champeil-Potokar G, Hennebelle M, Lavialle M, Dutar P, Potier B, Billard JM, Vancassel S, Denis I (2013) Omega-3 fatty acids deficiency aggravates glutamatergic synapse and astroglial aging in the rat hippocampal CA1. Aging Cell 12:76–84. https://doi.org/10.1111/acel.12026
Potier B, Billard JM, Rivière S, Sinet PM, Denis I, Champeil-Potokar G, Grintal B, Jouvenceau A, Kollen M, Dutar P (2010) Reduction in glutamate uptake is associated with extrasynaptic NMDA and metabotropic glutamate receptor activation at the hippocampal CA1 synapse of aged rats. Aging Cell 9(5):722–735. https://doi.org/10.1111/j.1474-9726.2010.00593.x
Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8(6):595–608. https://doi.org/10.15252/emmm.201606210
McGeer PL, Rogers J, McGeer EG (2016) Inflammation, antiinflammatory agents, and Alzheimer’s disease: the last 22 years. J Alzheimers Dis 54(3):853–857
Vanderheyden WM, Lim MM, Musiek ES, Gerstner JR (2018) Alzheimer’s disease and sleep-wake disturbances: amyloid, astrocytes, and animal models. J Neurosci 38(12):2901–2910. https://doi.org/10.1523/jneurosci.1135-17.2017
Furukawa K, Abe Y, Akaike N (1994) Amyloid beta protein-induced irreversible current in rat cortical neurones. NeuroReport 5(16):2016–2018
Yan SD, Fu J, Soto C, Chen X, Zhu H, Al-Mohanna F, Collison K, Zhu A, Stern E, Saido T, Tohyama M, Ogawa S, Roher A, Stern D (1997) An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer’s disease. Nature 389(6652):689–695
Hansen DV, Hanson JE, Sheng M (2017) Microglia in Alzheimer’s disease. J Cell Biol. https://doi.org/10.1083/jcb.201709069
Rajendran L, Paolicelli RC (2018) Microglia-mediated synapse loss in Alzheimer’s disease. J Neurosci 38(12):2911–2919. https://doi.org/10.1523/jneurosci.1136-17.2017
Liu HP, Lin WY, Liu SH, Wang WF, Tsai CH, Wu BT, Wang CK, Tsai FJ (2009) Genetic variation in N-methyl-d-aspartate receptor subunit NR3A but not NR3B influences susceptibility to Alzheimer’s disease. Dement Geriatr Cogn Disord 28(6):521–527
EndeleS RosenbergerG, Geider K, Popp B, Tamer C, Stefanova I, Milh M, Kortüm F, Fritsch A, Pientka FK, Hellenbroich Y, Kalscheuer VM, Kohlhase J, Moog U, Rappold G, Rauch A, Ropers HH, von Spiczak S, Tönnies H, Villeneuve N, Villard L, Zabel B, Zenker M, Laube B, Reis A, Wieczorek D, Van Maldergem L, Kutsche K (2010) Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 42(11):1021–1026. https://doi.org/10.1038/ng.677
ZhangY LiP, Feng J, Wu M (2016) Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci 37(7):1039–1047. https://doi.org/10.1007/s10072-016-2546-5
SoniN ReddyBV, Kumar P (2014) GLT-1 transporter: an effective pharmacological target for various neurological disorders. Pharmacol Biochem Behav 127:70–81. https://doi.org/10.1016/j.pbb.2014.10.001
Syková E, Vorísek I, Antonova T, Mazel T, Meyer-Luehmann M, Jucker M, Hájek M, Ort M, Bures J (2005) Changes in extracellular space size and geometry in APP23 transgenic mice: a model of Alzheimer’s disease. Proc Natl Acad Sci USA 102(2):479–484
Sidoryk-Wegrzynowicz M, Gerber YN, Ries M, Sastre M, Tolkovsky AM, Spillantini MG (2017) Astrocytes in mouse models of tauopathies acquire early deficits and lose neurosupportive functions. Acta Neuropathol Commun. 5(1):89. https://doi.org/10.1186/s40478-017-0478-9
Huang S, Tong H, Lei M, Zhou M, Guo W, Li G, Tang X, Li Z, Mo M, Zhang X, Chen X, Cen L, Wei L, Xiao Y, Li K, Huang Q, Yang X, Liu W, Zhang L, Qu S, Li S, Xu P (2018) Astrocytic glutamatergic transporters are involved in Aβ-induced synaptic dysfunction. Brain Res 1678:129–137. https://doi.org/10.1016/j.brainres.2017.10.011
Hoshi A, Tsunoda A, Yamamoto T, Tada M, Kakita A, Ugawa Y (2018) Altered expression of glutamate transporter-1 and water channel protein aquaporin-4 in human temporal cortex with Alzheimer’s disease. Neuropathol Appl Neurobiol. https://doi.org/10.1111/nan.12475
Feigin VL, Barker-Collo S, Krishnamurthi R, Theadom A, Starkey N (2010) Epidemiology of ischaemic stroke and traumatic brain injury. Best Pract Res Clin Anaesthesiol 24(4):485–494. https://doi.org/10.1016/j.bpa.2010.10.006
Heiss WD (2012) The ischemic penumbra: how does tissue injury evolve? Ann N Y Acad Sci 1268:26–34. https://doi.org/10.1111/j.1749-6632.2012.06668.x
Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22(9):391–397
Somjen GG (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol Rev 81(3):1065–1096
Dorsett CR, McGuire JL, DePasquale EA, Gardner AE, Floyd CL, McCullumsmith RE (2017) Glutamate neurotransmission in rodent models of traumatic brain injury. J Neurotrauma 34(2):263–272. https://doi.org/10.1089/neu.2015.4373
Jia SW, Liu XY, Wang SC, Wang YF (2016) Vasopressin hypersecretion-associated brain edema formation in ischemic stroke: underlying mechanisms. J Stroke Cerebrovasc Dis 25(6):1289–1300
Leao AAP (1944) Spreading depression of activity in the cerebral cortex. J Neurophysiol 7:359–390
Somjen GG (2005) Aristides Leão’s discovery of cortical spreading depression. J Neurophysiol 94(1):2–4
Dreier JP (2011) The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17(4):439–447
Kramer DR, Fujii T, Ohiorhenuan I, Liu CY (2016) Cortical spreading depolarization: Pathophysiology, implications, and future directions. J Clin Neurosci 24:22–27. https://doi.org/10.1016/j.jocn.2015.08.004
Hartings JA, Rolli ML, Lu XC, Tortella FC (2003) Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: relation to infarct growth and neuroprotection. J Neurosci 23(37):11602–11610
Dohmen C, Sakowitz OW, Fabricius M, Bosche B, Reithmeier T, Ernestus RI, Brinker G, Dreier JP, Woitzik J, Strong AJ, Graf R, Co-Operative Study of Brain Injury Depolarisations (COSBID) (2008) Spreading depolarizations occur in human ischemic stroke with high incidence. Ann Neurol. 63(6):720–728. https://doi.org/10.1002/ana.21390
Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ (2011) Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab 31(1):17–35. https://doi.org/10.1038/jcbfm.2010.191
Mies G, Iijima T, Hossmann KA (1993) Correlation between peri-infarct DC shifts and ischaemic neuronal damage in rat. NeuroReport 4(6):709–711
Hartings JA, Rolli ML, Lu XC, Tortella FC (2003) Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: relation to infarct growth and neuroprotection. J Neurosci 23(37):11602–11610
Madl JE, Burgesser K (1993) Adenosine triphosphate depletion reverses sodium-dependent, neuronal uptake of glutamate in rat hippocampal slices. J Neurosci 13(10):4429–4444
Storm-Mathisen J, Danbolt NC, Rothe F, Torp R, Zhang N, Aas JE, Kanner BI, Langmoen I, Ottersen OP (1992) Ultrastructural immunocytochemical observations on the localization, metabolism and transport of glutamate in normal and ischemic brain tissue. Prog Brain Res 94:225–241
Song M, Yu SP (2014) Ionic regulation of cell volume changes and cell death after ischemic stroke. Transl Stroke Res 5(1):17–27. https://doi.org/10.1007/s12975-013-0314-x
Pasantes-Morales H, Tuz K (2006) Volume changes in neurons: hyperexcitability and neuronal death. Contrib Nephrol 152:221–240
Kimelberg HK (2005) Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia 50(4):389–397
Hyzinski-García MC, Vincent MY, Haskew-Layton RE, Dohare P, Keller RW Jr, Mongin AA (2011) Hypo-osmotic swelling modifies glutamate-glutamine cycle in the cerebral cortex and in astrocytecultures. J Neurochem 118(1):140–152. https://doi.org/10.1111/j.1471-4159.2011.07289.x
Haskew-Layton RE, Rudkouskaya A, Jin Y, Feustel PJ, Kimelberg HK, Mongin AA (2008) Two distinct modes of hypoosmotic medium-induced release of excitatory amino acids and taurine in the rat brain in vivo. PLoS One 3(10):e3543
Rovegno M, Sáez JC (2018) Role of astrocyte connexin hemichannels in cortical spreading depression. Biochim Biophys Acta 1860(1):216–223. https://doi.org/10.1016/j.bbamem.2017.08.014
Hu YY, Xu J, Zhang M, Wang D, Li L, Li WB (2015) Ceftriaxone modulates uptake activity of glial glutamate transporter-1 against global brain ischemia in rats. J Neurochem 132(2):194–205. https://doi.org/10.1111/jnc.12958
Becerra-Calixto A, Cardona-Gómez GP (2017) The role of astrocytes in neuroprotection after brain stroke: potential in cell therapy. Front Mol Neurosci 10:88. https://doi.org/10.3389/fnmol.2017.00088
Wu DC, Chen RY, Cheng TC, Chiang YC, Shen ML, Hsu LL, Zhou N (2017) Spreading depression promotes astrocytic calcium oscillations and enhances gliotransmission to hippocampal neurons. Cereb Cortex 1:1–13. https://doi.org/10.1093/cercor/bhx192
Seidel JL, Escartin C, Ayata C, Bonvento G, Shuttleworth CW (2016) Multifaceted roles for astrocytes in spreading depolarization: a target for limiting spreadingdepolarization in acute brain injury? Glia 64(1):5–20. https://doi.org/10.1002/glia.22824
Liu Z, Chopp M (2016) Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog Neurobiol 144:103–120. https://doi.org/10.1016/j.pneurobio.2015.09.008
Li Y, Liu Z, Xin H, Chopp M (2014) The role of astrocytes in mediating exogenous cell-based restorative therapy for stroke. Glia 62(1):1–16. https://doi.org/10.1002/glia.22585
Basarsky TA, Duffy SN, Andrew RD, MacVicar BA (1998) Imaging spreading depression and associated intracellular calcium waves in brain slices. J Neurosci 18(18):7189–7199
Smith JM, Bradley DP, James MF, Huang CL (2006) Physiological studies of cortical spreading depression. Biol Rev Camb Philos Soc 81(4):457–481
Marklund N, Hillered L (2011) Animal modelling of traumatic brain injury in preclinical drug development: where do we go from here? Br J Pharmacol 164(4):1207–1229. https://doi.org/10.1111/j.1476-5381.2010.01163.x
Walz W, Wuttke WA (1999) Independent mechanisms of potassium clearance by astrocytes in gliotic tissue. J Neurosci Res 56(6):595–603
D’Ambrosio R, Gordon DS, Winn HR (2002) Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K(+) in rat hippocampus. J Neurophysiol 87(1):87–102
Torrente D, Cabezas R, Avila MF, García-Segura LM, Barreto GE, Guedes RC (2014) Cortical spreading depression in traumatic brain injuries: is there a role for astrocytes? Neurosci Lett 565:2–6. https://doi.org/10.1016/j.neulet.2013.12.058
Somjen GG, Segal MB, Herreras O (1991) Osmotic-hypertensive opening of the blood-brain barrier in rats does not necessarily provide access for potassium to cerebral interstitial fluid. Exp Physiol 76(4):507–514
Tang YT, Mendez JM, Theriot JJ, Sawant PM, López-Valdés HE, Ju YS, Brennan KC (2014) Minimum conditions for the induction of cortical spreading depression in brain slices. J Neurophysiol 112(10):2572–2579. https://doi.org/10.1152/jn.00205.2014
Lapilover EG, Lippmann K, Salar S, Maslarova A, Dreier JP, Heinemann U, Friedman A (2012) Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges. Neurobiol Dis 48(3):495–506
Brassai A, Suvanjeiev RG, Bán EG, Lakatos M (2015) Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity. Brain Res Bull 112:1–6. https://doi.org/10.1016/j.brainresbull.2014.12.007
Mckee AC, Daneshvar DH (2015) The neuropathology of traumatic brain injury. Handb Clin Neurol 127:45–66. https://doi.org/10.1016/b978-0-444-52892-6.00004-0
da Silva Meirelles L, Simon D, Regner A (2017) Neurotrauma: the crosstalk between neurotrophins and inflammation in the acutely injured brain. Int J Mol Sci. https://doi.org/10.3390/ijms18051082
Winkler EA, Minter D, Yue JK, Manley GT (2016) Cerebral edema in traumatic brain injury: pathophysiology and prospective therapeutic targets. Neurosurg Clin N Am 27(4):473–488. https://doi.org/10.1016/j.nec.2016.05.008
Algattas H, Huang JH (2013) Traumatic Brain Injury pathophysiology and treatments: early, intermediate, and late phases post-injury. Int J Mol Sci 15(1):309–341. https://doi.org/10.3390/ijms15010309
McGinn MJ, Povlishock JT (2016) Pathophysiology of traumatic brain injury. Neurosurg Clin N Am 27(4):397–407. https://doi.org/10.1016/j.nec.2016.06.002
Chang BS, Lowenstein DH (2003) Epilepsy. N Engl J Med 349(13):1257–1266
Wetherington J, Serrano G, Dingledine R (2008) Astrocytes in the epileptic brain. Neuron 58(2):168–178. https://doi.org/10.1016/j.neuron.2008.04.002
Wolfart J, Laker D (2015) Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential. Front Physiol 6:168. https://doi.org/10.3389/fphys.2015.00168
Hinterkeuser S, Schröder W, Hager G, Seifert G, Blümcke I, Elger CE, Schramm J, Steinhäuser C (2000) Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances. Eur J Neurosci 12(6):2087–2096
Bedner P, Dupper A, Hüttmann K, Müller J, Herde MK, Dublin P, Deshpande T, Schramm J, Häussler U, Haas CA, Henneberger C, Theis M, Steinhäuser C (2015) Astrocyte uncoupling as a cause of human temporal lobe epilepsy. 138(Pt 5):1208–1222. https://doi.org/10.1093/brain/awv067
Cavus I, Kasoff WS, Cassaday MP, Jacob R, Gueorguieva R, Sherwin RS, Krystal JH, Spencer DD, Abi-Saab WM (2005) Extracellular metabolites in the cortex and hippocampus of epileptic patients. Ann Neurol 57(2):226–235
Petroff OA, Errante LD, Rothman DL, Kim JH, Spencer DD (2002) Neuronal and glial metabolite content of the epileptogenic human hippocampus. Ann Neurol 52(5):635–642
Coulter DA, Eid T (2012) Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60(8):1215–1226. https://doi.org/10.1002/glia.22341
During MJ, Spencer DD (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341:1607–1610
Eid T, Thomas MJ, Spencer DD, Runden-Pran E, Lai JC, Malthankar GV, Kim JH, Danbolt NC, Ottersen OP, de Lanerolle NC (2004) Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363:28–37
van der Hel WS, Notenboom RG, Bos IW, van Rijen PC, van Veelen CW, de Graan PN (2005) Reduced glutamine synthetase in hippocampal areas with neuron loss in temporal lobe epilepsy. Neurology 64:326–333
Mathern GW, Mendoza D, Lozada A, Pretorius JK, Dehnes Y, Danbolt NC, Nelson N, Leite JP, Chimelli L, Born DE, Sakamoto AC, Assirati JA, Fried I, Peacock WJ, Ojemann GA, Adelson PD (1999) Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology 52:453–472
Proper EA, Hoogland G, Kappen SM, Jansen GH, Rensen MG, Schrama LH, van Veelen CW, van Rijen PC, van Nieuwenhuizen O, Gispen WH, de Graan PN (2002) Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 125:32–43
Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699–1702
Watanabe T, Morimoto K, Hirao T, Suwaki H, Watase K, Tanaka K (1999) Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice. Brain Res 845(1):92–96
Kékesi O, Ioja E, Szabó Z, Kardos J, Héja L (2015) Recurrent seizure-like events are associated with coupled astroglial synchronization. Front Cell Neurosci 9:215. https://doi.org/10.3389/fncel.2015.00215
Boison D, Steinhäuser C (2017) Epilepsy and astrocyte energy metabolism. Glia. https://doi.org/10.1002/glia.23247
Chuang SC, Bianchi R, Wong RK (2000) Group I mGluR activation turns on a voltage-gated inward current in hippocampal pyramidal cells. J Neurophysiol 83(5):2844–2853
Chuang SC, Bianchi R, Kim D, Shin HS, Wong RK (2001) Group I metabotropic glutamate receptors elicit epileptiform discharges in the hippocampus through PLCbeta1 signaling. J Neurosci 21(16):6387–6394
Bianchi R, Chuang SC, Zhao W, Young SR, Wong RK (2009) Cellular plasticity for group I mGluR-mediated epileptogenesis. J Neurosci 29(11):3497–3507. https://doi.org/10.1523/jneurosci.5447-08.2009
Bianchi R, Wong RKS, Merlin LR (2012) Glutamate receptors in epilepsy: group I mGluR-mediated epileptogenesis. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US)
Merlin LR (2002) Differential roles for mGluR1 and mGluR5 in the persistent prolongation of epileptiform bursts. J Neurophysiol 87(1):621–625
O’Connor JJ, Rowan MJ, Anwyl R (1994) Long-lasting enhancement of NMDA receptor-mediated synaptic transmission by metabotropic glutamate receptor activation. Nature 367(6463):557–559
Laggerbauer B, Ostareck D, Keidel EM, Ostareck-Lederer A, Fischer U (2001) Evidence that fragile X mental retardation protein is a negative regulator of translation. Hum Mol Genet 10(4):329–338
Li Z, Zhang Y, Ku L, Wilkinson KD, Warren ST, Feng Y (2001) The fragile X mental retardation protein inhibits translation via interacting with mRNA. Nucleic Acids Res 29(11):2276–2283
Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27(7):370–377
Zhao W, Chuang SC, Young SR, Bianchi R, Wong RK (2015) Extracellular glutamate exposure facilitates group I mGluR-mediated epileptogenesis in the hippocampus. J Neurosci 35(1):308–315. https://doi.org/10.1523/jneurosci.1944-14.2015
Dölen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF (2007) Correction of fragile X syndrome in mice. Neuron 56(6):955–962
Rogawski MA (2013) AMPA receptors as a molecular target in epilepsy therapy. Acta Neurol Scand Suppl 197:9–18. https://doi.org/10.1111/ane.12099
Ghasemi M, Schachter SC (2011) The NMDA receptor complex as a therapeutic target in epilepsy: a review. Epilepsy Behav 22(4):617–640. https://doi.org/10.1016/j.yebeh.2011.07.024
Czéh B, Nagy SA (2018) Clinical findings documenting cellular and molecular abnormalities of glia indepressivedisorders. Front Mol Neurosci 11:56. https://doi.org/10.3389/fnmol.2018.00056 (eCollection 2018)
Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR, Gao K, Miskowiak KW, Grande I (2018) Bipolardisorders. Nat Rev Dis Primers 4:18008. https://doi.org/10.1038/nrdp.2018.8
Belujon P, Grace AA (2017) Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol 20(12):1036–1046. https://doi.org/10.1093/ijnp/pyx056
Haroon E, Miller AH, Sanacora G (2017) Inflammation, glutamate, and glia: atrio of trouble in mood disorders. Neuropsychopharmacology 42(1):193–215. https://doi.org/10.1038/npp.2016.199
Venero C, Borrell J (1999) Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats. Eur J Neurosci 11(7):2465–2473
Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M, Ellisman MH, Pekny M (2006) Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci USA 103(46):17513–17518
Hughes EG, Maguire JL, McMinn MT, Scholz RE, Sutherland ML (2004) Loss of glial fibrillary acidic protein results in decreased glutamate transport and inhibition of PKA-induced EAAT2 cell surface trafficking. Brain Res Mol Brain Res 124(2):114–123
Stertz L, Magalhães PV, Kapczinski F (2013) Is bipolar disorder an inflammatory condition? The relevance of microglial activation. Curr Opin Psychiatry 26(1):19–26. https://doi.org/10.1097/yco.0b013e32835aa4b4
Réus GZ, Fries GR, Stertz L, Badawy M, Passos IC, Barichello T, Kapczinski T, Quevedo J (2015) The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience 300:141–154. https://doi.org/10.1016/j.neuroscience.2015.05.018
Miller AH (2013) Conceptual confluence: the kynurenine pathway as a common target for ketamine and the convergence of the inflammation and glutamate hypotheses of depression. Neuropsychopharmacology 38(9):1607–1608. https://doi.org/10.1038/npp.2013.140
Santello M, Volterra A (2012) TNFα in synaptic function: switching gears. Trends Neurosci 35(10):638–647. https://doi.org/10.1016/j.tins.2012.06.001
Javitt DC (2010) Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci 47(1):4–16
Merritt K, Egerton A, Kempton MJ, Taylor MJ, McGuire PK (2016) Nature of glutamate alterations in schizophrenia: a meta-analysis of proton magnetic resonance spectroscopy studies. JAMA Psychiatry 73(7):665–674. https://doi.org/10.1001/jamapsychiatry.2016.0442
Karlsson RM, Tanaka K, Saksida LM, Bussey TJ, Heilig M, Holmes A (2009) Assessment of glutamate transporter GLAST (EAAT1)-deficient mice for phenotypes relevant to the negative and executive/cognitive symptoms of schizophrenia. Neuropsychopharmacology 34(6):1578–1589. https://doi.org/10.1038/npp.2008.215
Shan D, Yates S, Roberts RC, McCullumsmith RE (2012) Update on the neurobiology of schizophrenia: a role for extracellular microdomains. Minerva Psichiatr 53(3):233–249
O’Donovan SM, Sullivan CR, McCullumsmith RE (2017) The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders. NPJ Schizophr 3(1):32. https://doi.org/10.1038/s41537-017-0037-1
Bernstein HG, Steiner J, Guest PC, Dobrowolny H, Bogerts B (2015) Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy. Schizophr Res 161(1):4–18. https://doi.org/10.1016/j.schres.2014.03.035
Lander SS, Khan U, Lewandowski N, Chakraborty D, Provenzano FA, Mingote S, Chornyy S, Frigerio F, Maechler P, Kaphzan H, Small SA, Rayport S, Gaisler-Salomon I (2018) Glutamate dehydrogenase-deficient mice display schizophrenia-like behavioral abnormalities and CA1-specific hippocampal dysfunction. Schizophr Bull. https://doi.org/10.1093/schbul/sby011
Na KS, Jung HY, Kim YK (2014) The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 48:277–286. https://doi.org/10.1016/j.pnpbp.2012.10.022
Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10(8):561–572. https://doi.org/10.1038/nrn2515
Kalivas PW, McFarland K, Bowers S, Szumlinski K, Xi ZX, Baker D (2003) Glutamate transmission and addiction to cocaine. Ann N Y Acad Sci 1003:169–175
Baker DA, McFarland K, Lake RW, Shen H, Toda S, Kalivas PW (2003) N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci 1003:349–351
McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23(8):3531–3537
Scofield MD, Kalivas PW (2014) Astrocytic dysfunction and addiction: consequences of impaired glutamate homeostasis. Neuroscientist 20(6):610–622. https://doi.org/10.1177/1073858413520347
Hearing M, Graziane N, Dong Y, Thomas MJ (2018) Opioid and psychostimulant plasticity: targeting overlap in nucleus accumbens glutamate signaling. Trends Pharmacol Sci 39(3):276–294. https://doi.org/10.1016/j.tips.2017.12.004
Philogene-Khalid HL, Simmons SJ, Muschamp JW, Rawls SM (2017) Effects of ceftriaxone on conditioned nicotine reward in rats. Behav Pharmacol 28(6):485–488. https://doi.org/10.1097/fbp.0000000000000314
LaCrosse AL, O’Donovan SM, Sepulveda-Orengo MT, McCullumsmith RE, Reissner KJ, Schwendt M, Knackstedt LA (2017) Contrasting the role of xCT and GLT-1 upregulation in the ability of ceftriaxone to attenuate the cue-induced reinstatement of cocaine seeking and normalize AMPA receptor subunit expression. J Neurosci 37(24):5809–5821. https://doi.org/10.1523/jneurosci.3717-16.2017
Logan CN, LaCrosse AL, Knackstedt LA (2018) Nucleus accumbens GLT-1a overexpression reduces glutamate efflux during reinstatement of cocaine-seeking but is not sufficient to attenuate reinstatement. Neuropharmacology 135:297–307. https://doi.org/10.1016/j.neuropharm.2018.03.022
Alshehri FS, Hakami AY, Althobaiti YS, Sari Y (2018) Effects of ceftriaxone on hydrocodone seeking behavior and glial glutamate transporters in P rats. Behav Brain Res 347:368–376. https://doi.org/10.1016/j.bbr.2018.03.043
Sari Y, Sreemantula SN (2012) Neuroimmunophilin GPI-1046 reduces ethanol consumption in part through activation of GLT1 in alcohol-preferring rats. Neuroscience 227:327–335. https://doi.org/10.1016/j.neuroscience.2012.10.007
Gipson CD, Reissner KJ, Kupchik YM, Smith AC, Stankeviciute N, Hensley-Simon ME, Kalivas PW (2013) Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Proc Natl Acad Sci USA 110(22):9124–9129. https://doi.org/10.1073/pnas.1220591110
Fischer-Smith KD, Houston AC, Rebec GV (2012) Differential effects of cocaine access and withdrawal on glutamate type 1 transporter expression in rat nucleus accumbens core and shell. Neuroscience 210:333–339. https://doi.org/10.1016/j.neuroscience.2012.02.049
Wang J, Lanfranco MF, Gibb SL, Yowell QV, Carnicella S, Ron D (2010) Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse. J Neurosci 30(30):10187–10198. https://doi.org/10.1523/jneurosci.2268-10.2010
Shen H, Moussawi K, Zhou W, Toda S, Kalivas PW (2011) Heroin relapse requires long-term potentiation-like plasticity mediated by NMDA2b-containing receptors. Proc Natl Acad Sci USA 108(48):19407–19412. https://doi.org/10.1073/pnas.1112052108
Peters J, De Vries TJ (2012) Glutamate mechanisms underlying opiate memories. Cold Spring Harb Perspect Med. 2(9):a012088. https://doi.org/10.1101/cshperspect.a012088
Pomierny-Chamioło L, Rup K, Pomierny B, Niedzielska E, Kalivas PW, Filip M (2014) Metabotropic glutamatergic receptors and their ligands in drug addiction. Pharmacol Ther. 142(3):281–305. https://doi.org/10.1016/j.pharmthera.2013.12.012
Moussawi K, Kalivas PW (2010) Group II metabotropic glutamate receptors (mGlu2/3) in drug addiction. Eur J Pharmacol. 639(1–3):115–122. https://doi.org/10.1016/j.ejphar.2010.01.030
Meinhardt MW, Hansson AC, Perreau-Lenz S, Bauder-Wenz C, Stählin O, Heilig M, Harper C, Drescher KU, Spanagel R, Sommer WH (2013) Rescue of infralimbic mGluR2 deficit restores control over drug-seeking behavior in alcohol dependence. J Neurosci. 33(7):2794–2806. https://doi.org/10.1523/jneurosci.4062-12.2013
Bäckström P, Bachteler D, Koch S, Hyytiä P, Spanagel R (2004) mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology 29(5):921–928. https://doi.org/10.1038/sj.npp.1300381
Bespalov AY, Dravolina OA, Sukhanov I, Zakharova E, Blokhina E, Zvartau E, Danysz W, van Heeke G, Markou A (2005) Metabotropic glutamate receptor (mGluR5) antagonist MPEP attenuated cue- and schedule-induced reinstatement of nicotine self-administration behavior in rats. Neuropharmacology 49(Suppl 1):167–178. https://doi.org/10.1016/j.neuropharm.2005.06.007
Schroeder JP, Spanos M, Stevenson JR, Besheer J, Salling M, Hodge CW (2008) Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK1/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP. Neuropharmacology 55(4):546–554. https://doi.org/10.1016/j.neuropharm.2008.06.057
Gass JT, Osborne MP, Watson NL, Brown JL, Olive MF (2009) mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats. Neuropsychopharmacology 34(4):820–833. https://doi.org/10.1038/npp.2008.140
Kumaresan V, Yuan M, Yee J, Famous KR, Anderson SM, Schmidt HD, Pierce RC (2009) Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking. Behav Brain Res 202(2):238–244. https://doi.org/10.1016/j.bbr.2009.03.039
Sinclair CM, Cleva RM, Hood LE, Olive MF, Gass JT (2012) mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior. Pharmacol Biochem Behav 101(3):329–335. https://doi.org/10.1016/j.pbb.2012.01.014
Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang XJ, Arnsten AF (2013) NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron 77(4):736–749. https://doi.org/10.1016/j.neuron.2012.12.032
Li X, Peng XQ, Jordan CJ, Li J, Bi GH, He Y, Yang HJ, Zhang HY, Gardner EL, Xi ZX (2018) mGluR5 antagonism inhibits cocaine reinforcement and relapse by elevation of extracellular glutamate in the nucleus accumbens via a CB1 receptor mechanism. Sci Rep 8(1):3686. https://doi.org/10.1038/s41598-018-22087-1
Doshi A, Chataway J (2016) Multiple sclerosis, a treatable disease. Clin Med (Lond). 16(Suppl 6):s53–s59
Stojanovic IR, Kostic M, Ljubisavljevic S (2014) The role of glutamate and its receptors in multiple sclerosis. J Neural Transm (Vienna) 121(8):945–955. https://doi.org/10.1007/s00702-014-1188-0
Zindler E, Zipp F (2010) Neuronal injury in chronic CNS inflammation. Best Pract Res Clin Anaesthesiol 24(4):551–562. https://doi.org/10.1016/j.bpa.2010.11.001
Yawata I, Takeuchi H, Doi Y, Liang J, Mizuno T, Suzumura A (2008) Macrophage-induced neurotoxicity is mediated by glutamate and attenuated by glutaminase inhibitors and gap junction inhibitors. Life Sci. 82(21–22):1111–1116. https://doi.org/10.1016/j.lfs.2008.03.010
Piani D, Fontana A (1994) Involvement of the cystine transport system xc- in the macrophage-induced glutamate-dependent cytotoxicity to neurons. J Immunol 152(7):3578–3585
Tilleux S, Hermans E (2007) Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. J Neurosci Res 85(10):2059–2070. https://doi.org/10.1002/jnr.21325
Vercellino M, Merola A, Piacentino C, Votta B, Capello E, Mancardi GL, Mutani R, Giordana MT, Cavalla P (2007) Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J Neuropathol Exp Neurol 66(8):732–739
Gentile A, Musella A, De Vito F, Fresegna D, Bullitta S, Rizzo FR, Centonze D, Mandolesi G (2018) Laquinimod ameliorates excitotoxic damage by regulating glutamate re-uptake. J Neuroinflammation 15(1):5. https://doi.org/10.1186/s12974-017-1048-6
Matute C (2006) Oligodendrocyte NMDA receptors: a novel therapeutic target. Trends Mol Med 12(7):289–292. https://doi.org/10.1016/j.molmed.2006.05.004
Sulkowski G, Dąbrowska-Bouta B, Chalimoniuk M, Strużyńska L (2013) Effects of antagonists of glutamate receptors on pro-inflammatory cytokines in the brain cortex of rats subjected to experimental autoimmune encephalomyelitis. J Neuroimmunol 261(1–2):67–76. https://doi.org/10.1016/j.jneuroim.2013.05.006
Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87(3):493–506
Ghosh R, Tabrizi SJ (2015) Clinical aspects of Huntington’s disease.Curr Top. Behav Neurosci 22:3–31. https://doi.org/10.1007/7854_2013_238
Tong X, Ao Y, Faas GC, Nwaobi SE, Xu J, Haustein MD, Anderson MA, Mody I, Olsen ML, Sofroniew MV, Khakh BS (2014) Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat Neurosci 17(5):694–703. https://doi.org/10.1038/nn.3691
Ben Haim L, Ceyzériat K, Carrillo-de Sauvage MA, Aubry F, Auregan G, Guillermier M, Ruiz M, Petit F, Houitte D, Faivre E, Vandesquille M, Aron-Badin R, Dhenain M, Déglon N, Hantraye P, Brouillet E, Bonvento G, Escartin C (2015) The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer’s and Huntington’s diseases. J Neurosci 35(6):2817–2829. https://doi.org/10.1523/jneurosci.3516-14.2015
Jiang R, Diaz-Castro B, Looger LL, Khakh BS (2016) Dysfunctional calcium and glutamate signaling in striatal astrocytes from Huntington’s disease model mice. J Neurosci 36(12):3453–3470. https://doi.org/10.1523/jneurosci.3693-15.2016
Tsuang DW, Greenwood TA, Jayadev S, Davis M, Shutes-David A, Bird TD (2018) A genetic study of psychosis in Huntington’s disease: evidence for the involvement of glutamate signaling pathways. J Huntingtons Dis 7(1):51–59. https://doi.org/10.3233/jhd-170277
Parsons MP, Vanni MP, Woodard CL, Kang R, Murphy TH, Raymond LA (2016) Real-time imaging of glutamate clearance reveals normal striatal uptake in Huntington disease mouse models. Nat Commun 7:11251. https://doi.org/10.1038/ncomms11251
Gordon PH (2011) Amyotrophic lateral sclerosis: pathophysiology, diagnosis and management. CNS Drugs 25(1):1–15. https://doi.org/10.2165/11586000-000000000-00000
Vandenberghe W, Robberecht W, Brorson JR (2000) AMPAreceptorcalciumpermeability, GluR2 expression, and selectivemotoneuronvulnerability. J Neurosci 20(1):123–132
Van Damme P, Van Den Bosch L, Van Houtte E, Callewaert G, Robberecht W (2002) GluR2-dependent properties ofAMPAreceptors determine the selective vulnerability ofmotor neuronsto excitotoxicity. J Neurophysiol 88(3):1279–1287
Takuma H, Kwak S, Yoshizawa T, Kanazawa I (1999) Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis. Ann Neurol 46(6):806–815
Kawahara Y, Ito K, Sun H, Aizawa H, Kanazawa I, Kwak S (2004) Glutamate receptors: RNA editing and death of motor neurons. Nature 427(6977):801
Doble A (1996) The pharmacology and mechanism of action of riluzole. Neurology 47(6 Suppl 4):S233–S241
Albo F, Pieri M, Zona C (2004) Modulation of AMPA receptors in spinal motor neurons by the neuroprotective agent riluzole. J Neurosci Res 78(2):200–207. https://doi.org/10.1002/jnr.20244
Battaglia G, Bruno V (2018) Metabotropic glutamate receptor involvement in the pathophysiology of amyotrophic lateral sclerosis: new potential drug targets for therapeutic applications. Curr Opin Pharmacol 38:65–71. https://doi.org/10.1016/j.coph.2018.02.007
de Groot J, Sontheimer H (2011) Glutamate and the biology of gliomas. Glia 59(8):1181–1189. https://doi.org/10.1002/glia.21113
Maus A, Peters GJ (2017) Glutamate and α-ketoglutarate: key players in glioma metabolism. Amino Acids 49(1):21–32. https://doi.org/10.1007/s00726-016-2342-9
Ye ZC, Sontheimer H (1999) Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 59(17):4383–4391
Takano T, Lin JH, Arcuino G, Gao Q, Yang J, Nedergaard M (2001) Glutamate release promotes growth of malignant gliomas. Nat Med 7(9):1010–1015
Strong AD, Indart MC, Hill NR, Daniels RL (2018) GL261 glioma tumor cells respond to ATP with an intracellular calcium rise and glutamate release. Mol Cell Biochem. https://doi.org/10.1007/s11010-018-3272-5
Robert SM, Buckingham SC, Campbell SL, Robel S, Holt KT, Ogunrinu-Babarinde T, Warren PP, White DM, Reid MA, Eschbacher JM, Berens ME, Lahti AC, Nabors LB, Sontheimer H (2015) SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci Transl Med 7(289):289ra86. https://doi.org/10.1126/scitranslmed.aaa8103
Sørensen MF, Heimisdóttir SB, Sørensen MD, Mellegaard CS, Wohlleben H, Kristensen BW, Beier CP (2018) High expression of cystine-glutamate antiporter xCT (SLC7A11) is an independent biomarker for epileptic seizures at diagnosis in glioma. J Neurooncol. https://doi.org/10.1007/s11060-018-2785-9
Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, Watson DJ, Haydon PG, Coulter DA (2010) Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci 13(5):584–591. https://doi.org/10.1038/nn.2535
Zámecník J, Vargová L, Homola A, Kodet R, Syková E (2004) Extracellular matrix glycoproteins and diffusion barriers in human astrocytic tumours. Neuropathol Appl Neurobiol 30(4):338–350. https://doi.org/10.1046/j.0305-1846.2003.00541.x
Vargová L, Homola A, Zámecník J, Tichý M, Benes V, Syková E (2003) Diffusion parameters of the extracellular space in human gliomas. Glia 42(1):77–88. https://doi.org/10.1002/glia.10204
Savaskan NE, Heckel A, Hahnen E, Engelhorn T, Doerfler A, Ganslandt O, Nimsky C, Buchfelder M, Eyüpoglu IY (2008) Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema. Nat Med 14(6):629–632. https://doi.org/10.1038/nm1772
Morse AM, Garner DR (2018) Traumatic brain injury, sleep disorders, and psychiatric disorders: an underrecognized relationship. Med Sci (Basel). https://doi.org/10.3390/medsci6010015
Stangeland H, Orgeta V, Bell V (2018) Poststroke psychosis: a systematic review. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-2017-317327
Nucera A, Hachinski V (2018) Cerebrovascular and Alzheimer disease: fellow travelers or partners in crime? J Neurochem 144(5):513–516. https://doi.org/10.1111/jnc.14283
Klein P, Dingledine R, Aronica E, Bernard C, Blümcke I, Boison D, Brodie MJ, Brooks-Kayal AR, Engel J Jr, Forcelli PA, Hirsch LJ, Kaminski RM, Klitgaard H, Kobow K, Lowenstein DH, Pearl PL, Pitkänen A, Puhakka N, Rogawski MA, Schmidt D, Sillanpää M, Sloviter RS, Steinhäuser C, Vezzani A, Walker MC, Löscher W (2018) Commonalities in epileptogenic processes from different acute brain insults: do they translate? Epilepsia 59(1):37–66. https://doi.org/10.1111/epi.13965
Khokhar JY, Dwiel LL, Henricks AM, Doucette WT, Green AI (2018) The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res 194:78–85. https://doi.org/10.1016/j.schres.2017.04.016
Acknowledgements
The laboratory of the author was supported by the Hungarian National Brain Research Program (KTIA_13_NAP-A-I/10 to BP). The author is indebted to Péter Szücs for his valuable comments on the manuscript text; as well as to the members of the Laboratory for Neurobiology (Adrienn Kovács, Tsogbadrakh Bayasgalan, Ágnes Kovács and Brigitta Baksa) for the valuable discussions in the topic.
The author declares no competing financial interest.
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Pál, B. Involvement of extrasynaptic glutamate in physiological and pathophysiological changes of neuronal excitability. Cell. Mol. Life Sci. 75, 2917–2949 (2018). https://doi.org/10.1007/s00018-018-2837-5
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DOI: https://doi.org/10.1007/s00018-018-2837-5