Advertisement

Neurochemical Research

, Volume 39, Issue 1, pp 1–36 | Cite as

A Guide to the Metabolic Pathways and Function of Metabolites Observed in Human Brain 1H Magnetic Resonance Spectra

  • Caroline D. RaeEmail author
Overview

Abstract

The current knowledge of the normal biochemistry of compounds that give rise to resonances in human brain proton magnetic resonance spectra measureable at readily available field strengths (i.e. ≤3 T) is reviewed. Molecules covered include myo- and scyllo-inositol, glycerophospho- and phospho-choline and choline, creatine and phosphocreatine, N-acetylaspartate, N-acetylaspartylglutamate, glutamate, glutamine, γ-aminobutyrate, glucose, glutathione and lactate. The factors which influence changes in the levels of these compounds are discussed. As most proton resonances in the brain at low field are derived from a combination of moieties whose biochemistry is complex and interrelated, an understanding of the mechanisms underlying why these species change is crucial to meaningful interpretation of human brain spectra.

Keywords

N-acetylaspartate Choline Creatine Lactate myo-inositol γ-Aminobutyric acid 

Abbreviations

ASPA

Aspartoacylase

Cho

Choline-containing resonance

COSY

Correlation spectroscopy

Cre

Creatine-containing resonance

CRT

Creatine transporter

fMRS

Functional magnetic resonance spectroscopy

GABA

γ-Aminobutyric acid

GABA(A)R

GABA-A receptor

GABA(B)R

GABA B receptor

GAMT

Guanidinoacetate methyl transferase

GSH

Glutathione

GSSG

Oxidized glutathione

IQ

Intelligence quotient

MEGA-PRESS

Mescher–Garwood point resolved spectroscopy

NA

N-Acetyl containing resonance

NAA

N-Acetylaspartate

NAAG

N-Acetylaspartylglutamate

NAT8L

N-Acetyltransferase-8 like enzyme

NMDAR

N-Methyl-d-aspartate receptor

MRS

Magnetic resonance spectroscopy

PCr

Phosphocreatine

PRESS

Point-resolved spectroscopy

Notes

Acknowledgments

This work was supported by the National Health and Medical Research Council of Australia (Fellowship to CR). The author is grateful to Prof. Stephen R. Williams (The University of Manchester), to Assoc. Prof. Matthias Klugmann (The University of NSW), to Prof. Stefan Bröer (The Australian National University) and to Prof. John Griffiths (Cancer Research, UK) for critical appraisal of the manuscript.

References

  1. 1.
    Govindaraju V, Young K, Maudsley AA, Maudsley AA (2000) Proton NMR chemical shifts and coupling constant for brain metabolites. NMR Biomed 13:129–153PubMedGoogle Scholar
  2. 2.
    Kreis R, Bolliger CS (2012) The need for updates of spin system parameters, illustrated for the case of γ-aminobutyric acid. NMR Biomed 25:1401–1403Google Scholar
  3. 3.
    Tosi MR, Fini G, Tinti A, Reggiani A, Tugnoli V (2002) Molecular characterisation of human healthy and neoplastic cerebral and renal tissues by in vitro H-1NMR spectroscopy. Int J Mol Med 9:299–310PubMedGoogle Scholar
  4. 4.
    Kreis R (2004) Issues of spectral quality in clinical H-1-magnetic resonance spectroscopy and a gallery of artifacts. NMR Biomed 17:361–381PubMedGoogle Scholar
  5. 5.
    Mountford CE, Stanwell P, Lin A, Ramadan S, Ross B (2010) Neurospectroscopy: the past, present and future. Chem Rev 110:3060–3086PubMedGoogle Scholar
  6. 6.
    Choi CH, Ghose S, Uh J, Pate A, Dimitrov IE, Lu HZ, Douglas D, Ganjil S (2010) Measurement of N-acetylaspartylglutamate in the human frontal brain by (1)H-MRS at 7 T. Magn Reson Med 64:1247–1251PubMedCentralPubMedGoogle Scholar
  7. 7.
    Frahm J, Michaelis T, Merboldt K-D, Hänicke W, Gyngell ML, Bruhn H (1991) On the N-acetyl methyl resonance in localised 1 h NMR spectra of human brain in vivo. NMR Biomed 4:201–204PubMedGoogle Scholar
  8. 8.
    Pouwels PJW, Frahm J (1997) Differential distribution of NAA and NAAG in human brain as determined by quantitative localised proton MRS. NMR Biomed 10:73–79PubMedGoogle Scholar
  9. 9.
    Brooks JCW, Roberts N, Kemp GJ, Gosney MA, Lye M, Whitehouse GH (2001) A proton magnetic resonance spectroscopy study of age-related changes in frontal lobe metabolite concentrations. Cereb Cortex 11:598–605PubMedGoogle Scholar
  10. 10.
    Maudsley AA, Domenig C, Govind V, Darkazanli A, Studholme C, Bloomer C (2009) Mapping of brain metabolite distributions by volumetric proton MR spectroscopic imaging (MRSI). Magn Reson Med 61:548–559PubMedCentralPubMedGoogle Scholar
  11. 11.
    Niwa M, Nitta A, Mizoguchi H, Ito Y, Noda Y, Nagai T, Nabeshima T (2007) A novel molecule “Shati” is involved in methamphetamine-induced hyperlocomotion, sensitization, and conditioned place preference. J Neurosci 27:7604–7615PubMedGoogle Scholar
  12. 12.
    Wiame E, Tyteca D, Pierrot N, Collard F, Amyere M, Noel G, Desmedt J, Nassogne MC, Vikkula M, Octave JN, Vincent MF, Courtoy PJ, Boltshauser E, Van Schaftingen E (2010) Molecular identification of aspartate N-acetyltransferase and its mutation in hypoacetylaspartia. Biochem J 425:127–136Google Scholar
  13. 13.
    Patel TB, Clark JB (1979) Synthesis of N-acetyl-l-aspartate by rat brain mitochondria and its involvement in mitochondrial cytosolic carbon transport. Biochem J 184:539–546PubMedGoogle Scholar
  14. 14.
    Ariyannur PS, Moffett JR, Manickam P, Pattabiraman N, Arun P, Nitta A, Nabeshima T, Madhavarao CN, Namboodiri AMA (2010) Methamphetamine-induced neuronal protein NAT8L is the NAA biosynthetic enzyme: implications for specialized acetyl coenzyme A metabolism in the CNS. Brain Res 1335:1–13PubMedGoogle Scholar
  15. 15.
    Bhakoo KK, Pearce D (2000) In vitro expression of N-acetylaspartate by oligodendrocytes: implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 74:254–262PubMedGoogle Scholar
  16. 16.
    Tyson RL, Sutherland GR (1998) Labelling of N-acetylaspartate and N-acetylaspartylglutamate in rat neocortex, hippocampus and cerebellum from [1-13C]glucose. Neurosci Lett 251:181–184PubMedGoogle Scholar
  17. 17.
    Neale JH, Bzdega T, Wroblewska B (2000) N-acetylaspartylglutamate: the most abundant peptide neurotransmitter in the mammalian central nervous system. J Neurochem 75:443–452PubMedGoogle Scholar
  18. 18.
    Klugmann M, Symes CW, Klaussner BK, Leichtlein CB, Serikawa T, Young D, During MJ (2003) Identification and distribution of aspartoacylase in the postnatal rat brain. Neuro Report 14:1837–1840Google Scholar
  19. 19.
    Moffett JR, Arun P, Ariyannur PS, Garbern JY, Jacobowitz DM, Namboodiri AMA (2011) Extensive aspartoacylase expression in the rat central nervous system. Glia 59:1414–1434PubMedCentralPubMedGoogle Scholar
  20. 20.
    Chakraborty G, Mekala P, Yahya D, Wu G, Ledeen RW (2001) Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 78:736–745PubMedGoogle Scholar
  21. 21.
    Dadamo AF, Yatsu FM (1966) Acetate metabolism in nervous system. N-acetyl-l-aspartic acid and biosynthesis of brain lipids. J Neurochem 13:961–1000Google Scholar
  22. 22.
    Madhavarao CN, Arun P, Moffett JR, Szucs S, Surendran S, Matalon R, Garbern J, Hristova D, Johnson A, Jiang W, Namboodiri MAA (2005) Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan’s disease. Proc Natl Acad Sci USA 102:5221–5226PubMedGoogle Scholar
  23. 23.
    Hershfield JR, Madhavarao CN, Moffett JR, Benjamins JA, Garbern JY, Namboodiri A (2006) Aspartoacylase is a regulated nuclear-cytoplasmic enzyme. FASEB J 20:2139–2141PubMedGoogle Scholar
  24. 24.
    Kumar S, Biancotti JC, Matalon R, de Vellis J (2009) Lack of aspartoacylase activity disrupts survival and differentiation of neural progenitors and oligodendrocytes in a mouse model of canavan disease. J Neurosci Res 87:3415–3427PubMedGoogle Scholar
  25. 25.
    Francis JS, Strande L, Pu A, Leone P (2011) Endogenous aspartoacylase expression is responsive to glutamatergic activity in vitro and in vivo. Glia 59:1435–1446PubMedGoogle Scholar
  26. 26.
    Ariyannur PS, Moffett JR, Madhavarao CN, Arun P, Vishnu N, Jacobowitz DM, Hallows WC, Denu JM, Namboodiri AMA (2010) Nuclear-cytoplasmic localization of acetyl coenzyme a synthetase-1 in the rat brain. J Comp Neurol 518:2952–2977PubMedCentralPubMedGoogle Scholar
  27. 27.
    Francis JS, Strande L, Markov V, Leone P (2012) Aspartoacylase supports oxidative energy metabolism during myelination. J Cereb Blood Flow Metab 32:1725–1736Google Scholar
  28. 28.
    Moreno A, Ross BD, Blüml S (2001) Direct determination of the N-acetylaspartate synthesis rate in the human brain by 13C MRS and [1-13C]glucose infusion. J Neurochem 77:347–350PubMedGoogle Scholar
  29. 29.
    Bates TE, Strangwald M, Keelan J, Davey GP, Munro PM, Clarke JB (1996) Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo. Neuro Rep 7:1397–1400Google Scholar
  30. 30.
    Xu S, Yang J, Shen J (2008) Measuring N-acetylaspartate synthesis in vivo using proton magnetic resonance spectroscopy. J Neurosci Meth 172:8–12Google Scholar
  31. 31.
    Gomez R, Behar KL, Watzl J, Weinzimer SA, Gulanski B, Sanacora G, Koretski J, Guidone E, Jiang L, Petrakis IL, Pittman B, Krystal JH, Mason GF (2012) Intravenous ethanol infusion decreases human cortical γ-aminobutyric acid and N-acetylaspartate as measured with proton magnetic resonance spectroscopy at 4 Tesla. Biol Psychiatr 71:239–246Google Scholar
  32. 32.
    Sacha P, Zamecnik J, Barinka C, Hlouchova K, Vicha A, Mlcochova P, Hilgert I, Eckschlager T, Konvalinka J (2007) Expression of glutamate carboxypeptidase II in human brain. Neuroscience 144:1361–1372PubMedGoogle Scholar
  33. 33.
    Berger UV, Luthi-Carter R, Passani LA, Elkabes S, Black I, Konradi C, Coyle JT (1999) Glutamate carboxypeptidase II is expressed by astrocytes in the adult rat nervous system. J Comp Neurosci 415:52–64Google Scholar
  34. 34.
    Fujita T, Katsukawa H, Yodoya E, Wada M, Shimada A, Okada N, Yamamoto A, Ganapathy V (2005) Transport characteristics of N-acetyl-l-aspartate in rat astrocytes: involvement of sodium-coupled high-affinity carboxylate transporter NaC3/NaDC3-mediated transport system. J Neurochem 93:706–714PubMedGoogle Scholar
  35. 35.
    Yodoya E, Wada M, Shimada A, Katsukawa H, Okada N, Yamamoto A, Ganapathy V, Fujita T (2006) Functional and molecular identification of sodium-coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons. J Neurochem 97:162–173PubMedGoogle Scholar
  36. 36.
    Taylor DL, Davies SE, Obrenovitch TP, Urenjak J, Richards DA, Clark JB, Symon L (1994) Extracellular N-acetylaspartate in the rat brain: in vivo determination of basal levels and changes evoked by high K+. J Neurochem 62:2349–2355PubMedGoogle Scholar
  37. 37.
    Rahn KA, Watkins CC, Alt J, Rais R, Stathis M, Grishkan I, Crainiceau CM, Pomper MG, Rojas C, Pletnikov MV, Calabresi PA, Brandt J, Barker PB, Slusher BS, Kaplin AI (2012) Inhibition of glutamate carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis. Proc Natl Acad Sci USA 109:20101–20106PubMedGoogle Scholar
  38. 38.
    Gurkoff GG, Feng JF, Van KC, Izadi A, Ghiasvand R, Shahlaie K, Song M, Lowe DA, Zhou J, Lyeth BG (2013) NAAG peptidase inhibitor improves motor function and reduces cognitive dysfunction in a model of TBI with secondary hypoxia. Brain Res 1515:98–107PubMedGoogle Scholar
  39. 39.
    Nadler JV, Cooper JR (1972) N-Acetyl-l-aspartic acid content of human neural tumours and bovine peripheral nervous tissues. J Neurochem 19:313–319PubMedGoogle Scholar
  40. 40.
    Urenjak J, Williams SR, Gadian DG, Noble M (1992) Specific expression of N-acetylaspartate in neurons, oligodendrocyte type-2 progenitors and immature oligodendrocytes in vitro. J Neurochem 59:55–61PubMedGoogle Scholar
  41. 41.
    Urenjak J, Williams SR, Gadian DG, Noble M (1993) Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural types. J Neurosci 13:981–989PubMedGoogle Scholar
  42. 42.
    Demougeot C, Garnier P, Mossiat C, Bertrand N, Giroud M, Beley A, Marie C (2001) N-acetylaspartate, a marker of both cellular dysfunction and neuronal loss: its relevance to studies of acute brain injury. J Neurochem 77:408–415PubMedGoogle Scholar
  43. 43.
    Jenkins BG, Klivenyi P, Kustermann E, Andreassen OA, Ferrante RJ, Rosen BR, Beal MF (2000) Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington’s disease mice. J Neurochem 74:2108–2119PubMedGoogle Scholar
  44. 44.
    Rae C, Karmiloff-Smith A, Lee MA, Dixon RM, Grant J, Blamire AM, Thompson CH, Styles P, Radda GK (1998) Brain biochemistry in Williams syndrome: evidence for a role of the cerebellum in cognition? [see comments]. Neurology 51:33–40PubMedGoogle Scholar
  45. 45.
    Cheng LL, Newell K, Mallory AE, Hyman BT, Gonzalez RG (2002) Quantification of neurons in Alzheimer and control brains with ex vivo high resolution magic angle spinning proton magnetic resonance spectroscopy and stereology. Magn Reson Imag 20:527–533Google Scholar
  46. 46.
    Cheng LL, Ma MJ, Becerra L, Ptak T, Tracey I, Lackney A, Gonzalez RG (1997) Quantitative neuropathology by high resolution magic angle spinning proton magnetic resonance spectroscopy. Proc Nat Acad Sci USA 94:6408–6413PubMedGoogle Scholar
  47. 47.
    Sager TN, Topp S, Torup L, Hanson LG, Egestad B, Moller A (2001) Evaluation of CA1 damage using single-voxel H-1-MRS and un-biased stereology: can non-invasive measures of N-acetyl-aspartate following global ischemia be used as a reliable measure of neuronal damage? Brain Res 892:166–175PubMedGoogle Scholar
  48. 48.
    Baslow MH (2000) Functions of N-acetyl-l-aspartate and N-acetyl-l-aspartylglutamate in the vertebrate brain: role in glial cell-specific signalling. J Neurochem 75:453–459PubMedGoogle Scholar
  49. 49.
    Bothwell JH, Rae C, Dixon RM, Styles P, Bhakoo KK (2001) Hypo-osmotic swelling activated release of organic osmolytes in brain slices—implications for brain oedema in vivo. J Neurochem 77:1632–1640PubMedGoogle Scholar
  50. 50.
    Taylor DL, Davies SEC, Obrenovitch TP, Doheny MH, Patsalos PN, Clark JB, Symon L (1995) Investigation in the the role of N-acetylaspartate in cerebral osmoregulation. J Neurochem 65:275–281PubMedGoogle Scholar
  51. 51.
    Baslow MH, Hrabe J, Guilfoyle DN (2007) Dynamic relationship between neurostimulation and N-acetylaspartate metabolism in the human visual cortex. J Mol Neurosci 32:235–245PubMedGoogle Scholar
  52. 52.
    Baslow MH (2010) Evidence that the tri-cellular metabolism of N-acetylaspartate functions as the brain’s “operating system”: how NAA metabolism supports meaningful intercellular frequency-encoded communications. Amino Acid 39:1139–1145Google Scholar
  53. 53.
    Mangia S, Tkac I (2008) Letter to the editor. J Mol Neurosci 35:245–246PubMedGoogle Scholar
  54. 54.
    Nakada T (2010) Conversion of brain cytosol profile from fetal to adult type during the perinatal period: taurine-NAA exchange. Proc Jpn Acad Ser B-Phys Biol Sci 86:630–642PubMedCentralPubMedGoogle Scholar
  55. 55.
    Mersmann N, Tkachev D, Jelinek R, Roth PT, Mobius W, Ruhwedel T, Ruhle S, Weber-Fahr W, Sartorius A, Klugmann M (2011) Aspartoacylase-LacZ Knockin mice: an engineered model of canavan disease. PLoS One 6Google Scholar
  56. 56.
    Irwan R, Sijens PE, Potze JH, Oudkerk M (2005) Correlation of proton MR spectroscopy and diffusion tensor imaging. Magn Reson Imag 23:851–858Google Scholar
  57. 57.
    Destefano N, Matthews PM, Arnold DL (1995) Reversible decreases in N-acetylaspartate after acute brain injury. Magn Reson Med 34:721–727Google Scholar
  58. 58.
    Tonon C, Vetrugno R, Lodi R, Gallassi R, Provini F, Iotti S, Plazzi G, Montagna P, Lugaresi E, Barbiroli B (2007) Proton magnetic resonance spectroscopy study of brain metabolism in obstructive sleep apnoea syndrome before and after continuous positive airway pressure treatment. Sleep 30:305–311PubMedGoogle Scholar
  59. 59.
    Ferini-Strambi L, Baietto C, Di Gioia MR, Castaldi P, Castronovo C, Zucconi M, Cappa SR (2003) Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP). Brain Res Bull 61:87–92PubMedGoogle Scholar
  60. 60.
    Hashimoto T, Tayama M, Miyazaki M, Yoneda Y, Yoshimoto T, Harada M, Miyoshi H, Tanouchi M, Kuroda Y (1995) Reduced N-acetylaspartate in the brain observed on in vivo proton magnetic resonance spectroscopy in patients with mental retardation. Ped Neurol 13:205–208Google Scholar
  61. 61.
    Gadian DG, Isaacs EB, Cross JH, Connelly A, Jackson GD, King MD, Neville BGR, Varghakhadem F (1996) Lateralisation of brain function in childhood revealed by magnetic resonance spectroscopy. Neurology 46:974–977PubMedGoogle Scholar
  62. 62.
    Jung RE, Brooks WM, Yeo RA, Chiulli SJ, Weers C, Sibbitt WL (1999) Biochemical markers of intelligence: a proton MR spectroscopy study of normal human brain. Proc R Soc Lond B 266:1375–1379Google Scholar
  63. 63.
    Jung RE, Haier RJ, Yeo RA, Rowland LM, Petropoulos H, Levine AS, Sibbitt WL, Brooks WM (2005) Sex differences in N-acetylaspartate correlates of general intelligence: an H-1 MRS study of normal human brain. Neuroimage 26:965–972PubMedGoogle Scholar
  64. 64.
    Jung RE, Haier RJ (2007) The parieto-frontal integration theory (P-FIT) of intelligence: converging neuroimaging evidence. Behav Brain Sci 30:135–187PubMedGoogle Scholar
  65. 65.
    Rae C, Scott RB, Lee MA, Hines N, Paul C, Simpson JM, Karmiloff-Smith A, Anderson M, Styles P, Radda GK (2003) Brain bioenergetics and cognitive ability. Dev Neurosci 25:324–331PubMedGoogle Scholar
  66. 66.
    Martin E, Capone A, Schneider J, Hennig J, Thiel T (2001) Absence of N-acetylaspartate in the human brain: impact on neurospectroscopy? Ann Neurol 49:518–521PubMedGoogle Scholar
  67. 67.
    Boltshauser E, Schmitt B, Wevers RA, Engelke U, Burlina AB, Burlina AP (2004) Follow-up of a child with hypoacetylaspartia. Neuropediatr 35:255–258Google Scholar
  68. 68.
    Furukawa-Hibi Y, Nitta A, Fukumitsu H, Somiya H, Toriumi K, Furukawa S, Nabeshima T, Yamada K (2012) Absence of SHATI/Nat8 l reduces social interaction in mice. Neurosci Lett 526:79–84PubMedGoogle Scholar
  69. 69.
    Miller BL, Chang L, Booth R, Ernst T, Cornford M, Nikas D, McBride D, Jenden DJ (1996) In vivo 1H MRS: correlation with in vitro chemistry/histochemistry. Life Science 58:1929–1935Google Scholar
  70. 70.
    Barker PB, Breiter SN, Soher BJ, Chatham JC, Forder JR, Samphilipo MA, Magee CA, Anderson JH (1994) Quantitative proton spectroscopy of canine brain: in vivo and in vitro correlations. Magn Reson Med 32:157–163PubMedGoogle Scholar
  71. 71.
    Blüml S, Seymour KJ, Ross BD (1999) Developmental changes in choline- and ethanolamine-containing compounds measured with proton-decoupled 31P MRS in in vivo human brain. Magn Reson Med 42:643–654PubMedGoogle Scholar
  72. 72.
    Wurtman RJ (1992) Choline metabolism as a basis for the selective vulnerability of cholinergic neurons. Trends Neurosci 15:117–122PubMedGoogle Scholar
  73. 73.
    Löffelholz K, Klein J, Köppen A (1993) Choline, a precursor of acetylcholine and phospholipids in the brain. Prog Brain Res 98:197–200PubMedGoogle Scholar
  74. 74.
    Zeisel SH (1991) Choline, an essential nutrient for humans. FASEB J 5:2093–2098PubMedGoogle Scholar
  75. 75.
    Cornford EM, Braun LD, Oldendorf WH (1978) Carrier mediated blood-brain barrier transport of choline and certain choline analogues. J Neurochem 30:299–308PubMedGoogle Scholar
  76. 76.
    Aquilonius S-M, Ceder G, Lying-Tunell U, Malmlund HO, Schuberth J (1975) The arteriovenous difference of choline across the brain of man. Brain Res 99:430–433PubMedGoogle Scholar
  77. 77.
    Illingworth RD, Portman OW (1972) Uptake and metabolism of plasma lysophosphatidylcholine in vivo by brain of squirrel monkeys. Biochem J 130:557–1000PubMedGoogle Scholar
  78. 78.
    Ansell GB, Spanner S (1971) Studies on origin of choline in brain of rat. Biochem J 122:741–1000PubMedGoogle Scholar
  79. 79.
    Klein J, Koppen A, Loffelholz K, Schmitthenner J (1992) Uptake and metabolism of choline by rat-brain after acute choline administration. J Neurochem 58:870–876PubMedGoogle Scholar
  80. 80.
    Stoll AL, Renshaw PF, de Micheli E, Wurtman RJ, Pillay SS, Cohen BM (1995) Choline ingestion increases the resonance of choline-containing compounds in human brain: an in vivo proton magnetic resonance study. Biol Psychiatr 37:170–174Google Scholar
  81. 81.
    Dechent P, Pouwels PJW, Frahm J (1999) Neither short-term nor long-term adminstration of oral choline alters metabolite concentrations in human brain. Biol Psychiatr 46:406–411Google Scholar
  82. 82.
    Tan J, Bluml S, Hoang T, Dubowitz D, Mevenkamp G, Ross BD (1998) Lack of effect of oral choline supplementation on the concentrations of choline metabolites in human brain. Magn Reson Med 39:1005–1010PubMedGoogle Scholar
  83. 83.
    Babb SM, Ke Y, Lange N, Kaufman MJ, Renshaw PF, Cohen BM (2004) Oral choline increases choline metabolites in human brain. Psychiatr Res Neuroimag 130:1–9Google Scholar
  84. 84.
    Morley BJ, Fleck DL (1987) A time course and dose-response study of the regulation of brain nicotinic receptors by dietary choline. Brain Res 421:21–29PubMedGoogle Scholar
  85. 85.
    Hirsch MJ, Wurtman RJ (1978) Lecithin consumption increases acetylcholine concentrations in rat brain and adrenal gland. Science 202:223–225PubMedGoogle Scholar
  86. 86.
    Wang XC, Du XX, Tian Q, Wang JZ (2008) Correlation between choline signal intensity and acetylcholine level in different brain regions of rat. Neurochem Res 33:814–819PubMedGoogle Scholar
  87. 87.
    Poly C, Massaro JM, Seshadri S, Wolf PA, Cho EY, Krall E, Jacques PF, Au R (2011) The relation of dietary choline to cognitive performance and white-matter hyper intensity in the Framingham offspring cohort. Am J Clin Nutr 94:1584–1591PubMedGoogle Scholar
  88. 88.
    Yamamura HI, Snyder SH (1972) Choline: high-affinity uptake by rat brain synaptosomes. Science 178:626–628PubMedGoogle Scholar
  89. 89.
    Diamond I, Kennedy EP (1969) Carrier-mediated transport of choline into synaptic nerve endings. J Biol Chem 244:3258–3263PubMedGoogle Scholar
  90. 90.
    Kuharm MJ, Murrin LC (1978) Sodium-dependent, high affinity choline uptake. J Neurochem 30:15–21Google Scholar
  91. 91.
    Tucek S (1984) Problems in the organization and control of acetylcholine synthesis in brain neurons. Prog Biophys Mol Biol 44:1–46PubMedGoogle Scholar
  92. 92.
    Scremin OU, Jenden DJ (1993) Acetylcholine turnover and release: the influence of energy metabolism and systemic choline availability. Prog Brain Res 98:191–195PubMedGoogle Scholar
  93. 93.
    Michel V, Yuan ZF, Ramsubir S, Bakovic M (2006) Choline transport for phospholipid synthesis. Exp Biol Med 231:490–504Google Scholar
  94. 94.
    Aquilonius S-M, Windbladh B (1972) Cerebrospinal fluid clearance of choline and some other amines. Acta Physiol Scand 85:78–90PubMedGoogle Scholar
  95. 95.
    Mann SP, Hebb C (1977) Free choline in the brain of the rat. J Neurochem 28:241–244PubMedGoogle Scholar
  96. 96.
    Zeisel SH (2000) Choline: needed for normal development of memory. J Am Coll Nutr 19:528S–531SPubMedGoogle Scholar
  97. 97.
    Dainous F, Freysz L, Mozzi R, Dreyfus H, Louis JC, Porcellati G, Massarelli R (1982) Synthesis of choline phospholipids in neuronal and glial cell cultures by the methylation pathway. FEBS Lett 146:221–223PubMedGoogle Scholar
  98. 98.
    Lakher M, Wurtman RJ (1987) In vivo synthesis of phosphatidylcholine in rat brain via the phospholipid methylation pathway. Brain Res 419:131–140PubMedGoogle Scholar
  99. 99.
    Jenden DJ (1991) The metabolism of choline. Bull Clin Neurosci 55:99–106Google Scholar
  100. 100.
    Gibson GE, Blass JP (1976) Impaired synthesis of acetylcholine in brain accompanying mild hypoxia and hypoglycaemia. J Neurochem 27:37–42PubMedGoogle Scholar
  101. 101.
    Sartorius A, Schloss P, Vollmayr B, Ende G, Neumann-Haefelin C, Hoehn M, Henn FA (2006) Correlation between MR-spectroscopic rat hippocampal choline levels and phospholipase A2. World J Biol Psychiatr 7:246–250Google Scholar
  102. 102.
    Boulanger Y, Labelle M, Khiat A (2000) Role of phospholipase A(2) on the variations of the choline signal intensity observed by H-1 magnetic resonance spectroscopy in brain diseases. Brain Res Rev 33:380–389PubMedGoogle Scholar
  103. 103.
    Bhakoo KK, Williams SR, Florian CL, Land H, Noble M (1996) Immortalisation and transformation are associated with specific alterations in choline metabolism. Cancer Res 56:4630–4635PubMedGoogle Scholar
  104. 104.
    Laule C, Vavasour IM, Kolind SH, Li DKB, Traboulsee TL, Moore GRW, MacKay AL (2007) Magnetic resonance imaging of myelin. Neurotherapeutics 4:460–484PubMedGoogle Scholar
  105. 105.
    Martin PR, Gibbs SJ, Nimmerrichter AA, Riddle WR, Welch LW, Willcott MR (1995) Brain proton magnetic resonance spectroscopy studies in recently abstinent alcoholics. Alcohol Clin Exp Res 19:1078–1082PubMedGoogle Scholar
  106. 106.
    Jung RE, Yeo RA, Love TM, Petropoulos H, Sibbitt WL, Brooks WM (2002) Biochemical markers of mood: a proton magnetic resonance study of normal human brain. Biol Psychiatr 51:224–229Google Scholar
  107. 107.
    Craig MC, Daly EM, O’Gorman R, Rymer J, Lythgoe D, Ng G, Simmons A, Maki PM, Murphy DGM (2007) Effects of acute ovarian hormone suppression on the human brain: an in vivo H-1 MRS study. Psychoneuroendocrinology 32:1128–1132PubMedGoogle Scholar
  108. 108.
    Xiong QA, Du F, Zhu XH, Zhang PY, Suntharalingam P, Ippolito J, Kamdar FD, Chen W, Zhang JY (2011) ATP production rate via creatine kinase or ATP synthase in vivo a novel superfast magnetization saturation transfer method. Circ Res 108:U265–U653Google Scholar
  109. 109.
    Chen W, Zhu X-H, Adriany G, Ugurbil K (1997) Increase of creatine kinase activity in the visual cortex of human brain during visual stimulation: a 31P NMR magnetization transfer study. Magn Reson Med 38:551–557PubMedGoogle Scholar
  110. 110.
    Kruiskamp MJ, van Vliet G, Nicolay K (2000) 1H and 31P magnetization transfer studies of hindleg muscle in wild-type and creatine kinase-deficient mice. Magn Reson Med 43:657–664PubMedGoogle Scholar
  111. 111.
    Ke Y, Cohen BM, Lowen S, Hirashima F, Nassar L, Renshaw PF (2002) Biexponential transverse relaxation (T2) of the proton MRS creatine resonance in human brain. Magn Reson Med 47:232–238PubMedGoogle Scholar
  112. 112.
    Simister RJ, McLean MA, Salmenpera TM, Barker GJ, Duncan JS (2008) The effect of epileptic seizures on proton MRS visible neurochemical concentrations. Epilepsy Res 81:36–43PubMedGoogle Scholar
  113. 113.
    Dreher W, Norris DG, Leibfritz D (1994) Magnetization transfer affects the proton creatine/phosphocreatine signal intensity: in vivo demonstration in the rat brain. Magn Reson Med 31:81–84PubMedGoogle Scholar
  114. 114.
    Helms G, Frahm J (1999) Magnetization transfer attenuation of creatine resonances in localised proton MRS of human brain in vivo. NMR Biomed 12:490–494PubMedGoogle Scholar
  115. 115.
    Kruiskamp MJ, de Graaf RA, van der Grond J, Lamerichs R, Nicolay K (2001) Magnetic coupling between water and creatine protons in human brain and skeletal muscle, as measured using inversion transfer H-1-MRS. NMR Biomed 14:1–4PubMedGoogle Scholar
  116. 116.
    Opstad KS, Bell BA, Griffiths JR, Howe FA (2008) An assessment of the effects of sample ischaemia and spinning time on the metabolic profile of brain tumour biopsy specimens as determined by high-resolution magic angle spinning H-1 NMR. NMR Biomed 21:1138–1147PubMedGoogle Scholar
  117. 117.
    Dechent P, Pouwels PJW, Wilken B, Hanefeld F, Frahm J (1999) Increase of total creatine in human brain after oral supplementation of creatine-monohydrate. Am J Physiol 277:R698–R704PubMedGoogle Scholar
  118. 118.
    Braissant O, Henry HML, Eilers B, Bachmann C (2001) Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Mol Brain Res 86:193–201PubMedGoogle Scholar
  119. 119.
    Defalco AJ, Davies RK (1961) The synthesis of creatine by the brain of the intact rat. J Neurochem 7:308–312PubMedGoogle Scholar
  120. 120.
    Dringen R, Verleysdonk S, Hamprecht B, Wilker W, Leibfritz D, Brand A (1998) Metabolism of glycine in primary astroglial cells: synthesis of creatine, serine and glutathione. J Neurochem 70:835–840PubMedGoogle Scholar
  121. 121.
    Braissant O, Henry H (2008) AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: a review. J Inherit Metab Dis 31:230–239PubMedGoogle Scholar
  122. 122.
    Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80:1107–1212PubMedGoogle Scholar
  123. 123.
    Stöckler S, Hanefeld F, Frahm J (1996) Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet 348:789–790PubMedGoogle Scholar
  124. 124.
    Valayannopoulos V, Boddaert N, Mention K, Touati G, Barbier V, Chabli A, Sedel F, Kaplan J, Dufier JL, Seidenwurm D, Rabier D, Saudubray JM, de Lonlay P (2009) Secondary creatine deficiency in ornithine delta-aminotransferase deficiency. Mol Genet Metab 97:109–113PubMedGoogle Scholar
  125. 125.
    Salomons GS, van Dooren SJM, Verhoeven NM, Cecil KM, Ball WS, Degrauw TJ, Jakobs C (2001) X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am J Hum Genet 68:1497–1500PubMedCentralPubMedGoogle Scholar
  126. 126.
    Chilosi A, Leuzzi V, Battini R, Tosetti M, Ferretti G, Comparini A, Casarano M, Moretti E, Alessandri MG, Bianchi MC, Cioni G (2008) Treatment with l-arginine improves neuropsychological disorders in a child with Creatine transporter defect. Neurocase 14:151–161PubMedGoogle Scholar
  127. 127.
    de Kamp JMV, Pouwels PJW, Aarsen FK, ten Hoopen LW, Knol DL, de Klerk JB, de Coo IF, Huijmans JGM, Jakobs C, van der Knaap MS, Salomons GS, Mancini GMS (2012) Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect. J Inherit Metab Dis 35:141–149PubMedCentralPubMedGoogle Scholar
  128. 128.
    Fons C, Sempere A, Arias A, Lopez-Sala A, Poo P, Pineda M, Mas A, Vilaseca MA, Salomons GS, Ribes A, Artuch R, Campistol J (2008) Arginine supplementation in four patients with X-linked creatine transporter defect. J Inherit Metab Dis 31:724–728PubMedGoogle Scholar
  129. 129.
    Valayannopoulos V, Boddaert N, Chabli A, Barbier V, Desguerre I, Philippe A, Afenjar A, Mazzuca M, Cheillan D, Munnich A, de Keyzer Y, Jakobs C, Salomons GS, de Lonlay P (2012) Treatment by oral creatine, l-arginine and l-glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis 35:151–157PubMedGoogle Scholar
  130. 130.
    Kurosawa Y, DeGrauw TJ, Lindquist DM, Blanco VM, Pyne-Geithman GJ, Daikoku T, Chambers JB, Benoit SC, Clark JF (2012) Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency. J Clin Invest 122:2837–2846PubMedCentralPubMedGoogle Scholar
  131. 131.
    Möller A, Hamprecht B (1989) Creatine transport in cultured cells of rat and mouse brain. J Neurochem 52:544–550PubMedGoogle Scholar
  132. 132.
    Braissant O, Henry H (2007) AGAT, GAMT and SLC6A8 distribution in the central nervous system, in relation to creatine deficiency syndromes: a review. In annual symposium of the society-for-the-study-of-inborn-errors-of-metabolism. Hamburg, Germany: SpringerGoogle Scholar
  133. 133.
    Braissant O, Beard E, Torrent C, Henry H (2010) Dissociation of AGAT, GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis 37:423–433PubMedGoogle Scholar
  134. 134.
    Dai WX, Vinnakota S, Qian XJ, Kunze DL, Sarkar HK (1999) Molecular characterization of the human CRT-1 creatine transporter expressed in xenopus oocytes. Arch Biochem Biophys 36:75–84Google Scholar
  135. 135.
    Dodd JR, Birch NP, Waldvogel HJ, Christie DL (2010) Functional and immunocytochemical characterization of the creatine transporter in rat hippocampal neurons. J Neurochem 115:684–693PubMedGoogle Scholar
  136. 136.
    Mak CSW, Waldvogel HJ, Dodd JR, Gilbert RT, Lowe MTJ, Birch NP, Faull RLM, Christie DL (2009) Immunohistochemical localisation of the creatine transporter in the rat brain. Neuroscience 163:571–585PubMedGoogle Scholar
  137. 137.
    Pyne-Geithman GJ, de Grauw TJ, Cecil KM, Chuck G, Lyons MA, Ishida Y, Clark JF (2004) Presence of normal creatine in the muscle of a patient with a mutation in the creatine transporter: a case study. Mol Cell Biochem 262:35–39PubMedGoogle Scholar
  138. 138.
    Nabuurs C, Romeijn M, Veltien A, Kan H, Isbrandt D, Heerschap A (2009) Creatine deficiency, uptake and breakdown studied in brain and muscle of Arginine:glycine Amidinotransferase deficient mice. Proc Int Soc Magn Reson Med 19:1026Google Scholar
  139. 139.
    Wilkinson ID, Mitchel N, Breivik S, Greenwood P, Griffiths PD, Winter EM, Van Beek EJR (2006) Effects of creatine supplementation on cerebral white matter in competitive sportsmen. Clin J Sport Med 16:63–67PubMedGoogle Scholar
  140. 140.
    McLean MA, Woermann FG, Barker GJ, Duncan JS (2000) Quantitative analysis of short echo time 1HMRSI of cerebral gray and white matter. Magn Reson Med 44:401–411PubMedGoogle Scholar
  141. 141.
    Pouwels PJW, Frahm J (1998) Regional metabolite concentrations in human brain as determined by quantitative localised proton MRS. Magn Reson Med 39:53–60PubMedGoogle Scholar
  142. 142.
    Kaldis P, Hemmer W, Zanolla E, Holtzman D, Walliman T (1996) ‘Hot spots’ of creatine kinase localisation in brain: cerebellum, hippocampus and choroid plexus. Dev Neurosci 18:542–554PubMedGoogle Scholar
  143. 143.
    Sartorius A, Lugenbiel P, Mahlstedt MM, Ende G, Schloss P, Vollmayr B (2008) Proton magnetic resonance spectroscopic creatine correlates with creatine transporter protein density in rat brain. J Neurosci Meth 172:215–219Google Scholar
  144. 144.
    Hertz L, Drejer J, Schousboe A (1988) Energy metabolism in glutamatergic neurons, GABAergic neurons and astrocytes in primary culture. Neurochem Res 13:605–610PubMedGoogle Scholar
  145. 145.
    Brand A, Richter-Lansberg C, Richter-Lansberg C, Leibfritz D (1993) Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 15:289–298PubMedGoogle Scholar
  146. 146.
    Lowe MTJ, Kim EH, Faull RLM, Christie DL, Waldvogel HJ (2013) Dissociated expression of mitochondrial and cytosolic creatine kinases in the human brain: a new perspective on the role of creatine in brain energy metabolism. J Cereb Blood Flow Metab 33:1295–1306PubMedGoogle Scholar
  147. 147.
    Tachikawa M, Fukaya M, Terasaki T, Ohtsuki S, Watanabe M (2004) Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis. Eur J Neurosci 20:144–160PubMedGoogle Scholar
  148. 148.
    Walliman T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzyme in tissues with high and fluctuating energy demands: the phosphocreatine circuit for cellular energy homeostasis. Biochem J 281:21–40Google Scholar
  149. 149.
    Rango M, Castelli A, Scarlato G (1997) Energetics of 3.5 s neural activation in humans: a 31P spectroscopy study. Magn Reson Med 38:878–883PubMedGoogle Scholar
  150. 150.
    Kemp GJ (2000) Non-invasive methods for studying brain energy metabolism: what they show and what it means. Dev Neurosci 22:418–428PubMedGoogle Scholar
  151. 151.
    Sappey-Marinier D, Calabrese G, Fein G, Hugg JW, Biggins C, Weiner MW (1992) Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab 12:584–592PubMedGoogle Scholar
  152. 152.
    Cox DWG, Morris PG, Feeney F, Bachelard HS (1983) 31P MRS studies on cerebral energy metabolism under conditions of hypoglycaemia and hypoxia in vitro. Biochem J 212:365–370PubMedGoogle Scholar
  153. 153.
    Sauter A, Rudin M (1993) Determination of creatine kinase kinetic parameters in rat brain by magnetization transfer. Correlation with brain function. J Biol Chem 268:13166–13171PubMedGoogle Scholar
  154. 154.
    t’Zandt HJAI, Jost C, Oerlemans F, Klomp DWJ, Wieringa B, Heerschap A (2000) Brains of creatine kinase deficient mice lack phosphocreatine and exhibit an increased NAA level. Proc Int Soc Magn Reson Med 8:174Google Scholar
  155. 155.
    Kekelidze T, Khait I, Togliatti A, Benzecry JM, Wieringa B, Holtzman D (1998) Altered brain phosphocreatine and ATP regulation when mitochondrial creatine kinase is absent. Wiley-Liss, Los AngelesGoogle Scholar
  156. 156.
    de Groof AJC, Oerlemans FTJJ, Jost CR, Wieringa B (2001) Changes in glycolytic network and mitochondrial design in creatine kinase-deficient muscles. Muscle Nerve 24:1188–1196PubMedGoogle Scholar
  157. 157.
    Rae C, Bartlett D, Yang Q, Walton D, Denotti A, Sachinwalla T, Grunstein RR (2009) Dynamic changes in brain bioenergetics during obstructive sleep apneoa. J Cereb Blood Flow Metab 29:1421–1428PubMedGoogle Scholar
  158. 158.
    Shoubridge EA, Briggs RW, Radda GK (1982) P-31 NMR saturation transfer measurements of the steady-state rates of creatine kinase and ATP synthetase in the rat brain. FEBS Lett 140:288–292Google Scholar
  159. 159.
    Holtzman D, Brown M, Ogorman E, Allred E, Wallimann T (1998) T Brain ATP metabolism in hypoxia resistant mice fed guanidinopropionic acid. Dev Neurosci 20:469–477PubMedGoogle Scholar
  160. 160.
    Holtzman D, Meyers R, Ogorman E, Khait I, Walliman T, Allred E, Jensen F (1997) In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog. Am J Physiol 41:C1567–C1577Google Scholar
  161. 161.
    Saks VA, Kongas O, Vendelin M, Kay L (2000) Role of the creatine/phosphocreatine system in the regulation of mitochondrial respiration. Acta Physiol Scand 168:635–641PubMedGoogle Scholar
  162. 162.
    Monge C, Beraud N, Kuznetsov AV, Rostovtseva T, Sackett D, Schlattner U, Vendelin M, Saks VA (2008) Regulation of respiration in brain mitochondria and synaptosomes: restrictions of ADP diffusion in situ, roles of tubulin, and mitochondrial creatine kinase. Mol Cell Biochem 318:147–165PubMedGoogle Scholar
  163. 163.
    Yoshizaki K, Watari H, Radda GK (1990) Role of phosphocreatine in energy-transport in skeletal muscle of bullfrog studied by P-31 NMR. Biochem Biophys Acta 1051:144–150PubMedGoogle Scholar
  164. 164.
    Kemp GJ, Manners DN, Clark JF, Bastin ME, Radda GK (1998) Theoretical modelling of some spatial and temporal aspects of the mitochondrion creatine kinase myofibril system in muscle. Mol Cell Biochem 184:249–289PubMedGoogle Scholar
  165. 165.
    Heilig CW, Stromski ME, Blumenfield JD, Lee JP, Gullans SR (1989) Characterization of the major brain osmolytes that accumulate in salt-loaded rats. Am J Physiol 257:F1108–F1116PubMedGoogle Scholar
  166. 166.
    Miller TJ, Hanson RD, Yancey PH (2000) Developmental changes in organic osmolytes in prenatal and postnatal rat tissues. Comp Biochem Physiol A 125:45–56Google Scholar
  167. 167.
    Bothwell JH, Styles P, Bhakoo KK (2002) Swelling-activated taurine and creatine effluxes from rat cortical astrocytes are pharmacologically distinct. J Membr Biol 185:157–164PubMedGoogle Scholar
  168. 168.
    Michaelis T, Wick M, Fujimori H, Matsumara A, Frahm J (1999) Proton MRS of oral creatine supplementation in rats. Cerebral metabolite concentration and ischemic challenge. NMR Biomed 12:309–314PubMedGoogle Scholar
  169. 169.
    Juhn MS, Tarnopolsky M (1998) Potential side effects of oral creatine supplementation: a critical review. Clin J Sport Med 8:298–304PubMedGoogle Scholar
  170. 170.
    Wyss M, Schulze A (2002) Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience 112:243–260PubMedGoogle Scholar
  171. 171.
    Watanabe A, Kato N, Kato T (2002) Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci Res 42:279–285PubMedGoogle Scholar
  172. 172.
    Rae C, Digney AL, McEwan SR, Bates TC (2003) Oral creatine monohydrate supplementation improves cognitive performance; a placebo-controlled, double blind, cross-over trial. Proc R Soc Lond B 279:2147–2150Google Scholar
  173. 173.
    Hammett ST, Wall MB, Edwards TC, Smith AT (2010) Dietary supplementation of creatine monohydrate reduces the human fMRI BOLD signal. Neurosci Lett 479:201–205PubMedGoogle Scholar
  174. 174.
    Almeida LS, Salomons GS, Hogenboom R, Jakobs C, Schoffelmeer ANM (2006) Exocytotic release of creatine in rat brain. Synapse 60:118–123PubMedGoogle Scholar
  175. 175.
    Koga Y, Takahashi H, Oikawa D, Tachibana T, Denbow DM, Furuse M (2005) Brain creatine functions to attenuate acute stress responses through gabaergic system in chicks. Neuroscience 132:65–71PubMedGoogle Scholar
  176. 176.
    de Deyn PP, Macdonald RL (1990) Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture. Ann Neurol 28:627–633PubMedGoogle Scholar
  177. 177.
    Neu A, Neuhoff H, Trube G, Fehr S, Ullrich K, Roeper J, Isbrandt D (2002) Activation of GABAA receptors by guanidinoacetate: a novel pathophysiological mechanism. Neurobiol Dis 11:298–307PubMedGoogle Scholar
  178. 178.
    Chebib M, Gavande N, Wong KY, Park A, Premoli I, Mewett KN, Allan RD, Duke RK, Johnston GAR, Hanrahan JR (2009) Guanidino acids act as rho 1 GABA(C) receptor antagonists. Neurochem Res 34:1704–1711PubMedGoogle Scholar
  179. 179.
    Royes LF, Fighera MR, Furian AF, Oliveira MS, Fiorenza NG, Ferreira J, da Silva AC, Priel MR, Ueda ES, Calixto JB, Cavalheiro EA, Mello CF (2008) Neuromodulatory effect of creatine on extracellular action potentials in rat hippocampus: role of NMDA receptors. Neurochem Int 53:33–37PubMedGoogle Scholar
  180. 180.
    Oliveira MS, Furian AF, Fighera MR, Fiorenza NG, Ferreira J, Rubin MA, Mello CF, Royes LFF (2008) The involvement of the polyamines binding sites at the NMDA receptor in creatine-induced spatial learning enhancement. Behav Brain Res 187:200–204PubMedGoogle Scholar
  181. 181.
    Genius J, Geiger J, Bender A, Moller H-J, Klopstock T, Rujescu D (2012) Creatine protects against excitotoxicity in an in vitro model of neurodegeneration. PLoS ONE 7:e30554PubMedCentralPubMedGoogle Scholar
  182. 182.
    Andres RH, Ducraya AD, Schlattner U, Wallimann T, Widmer HR (2008) Functions and effects of creatine in the central nervous system. Brain Res Bull 76:329–343PubMedGoogle Scholar
  183. 183.
    Jackson MC, Lenney JF (1996) The distribution of carnosine and related dipeptides in rat and human tissues. Inflamm Res 45:132–135PubMedGoogle Scholar
  184. 184.
    Petroff OAC, Hyder F, Rothman DL, Mattson RH (2000) Effects of gabapentin on brain GABA, homocarnosine and pyrrolidinone in epilepsy patients. Epilepsia 41:675–680PubMedGoogle Scholar
  185. 185.
    Keltner JR, Wald LL, Christensen JD, Maas LC, Moore CM, Cohen BM, Renshaw PF (1996) A technique for detecting GABA in the human brain with PRESS localization and optimized refocusing spectral editing radiofrequency pulses. Magn Reson Med 36:458–461PubMedGoogle Scholar
  186. 186.
    Rothman DL, Behar KL, Hetherington HP, Shulman RG (1984) Homonuclear H1 double resonance difference spectroscopy of the rat brain in vivo. Proc Nat Acad Sci United States Am-Biol Sci 81:6330–6334Google Scholar
  187. 187.
    Rothman DL, Petroff OAC, Behar KL, Mattson RH (1993) Localised 1H NMR measurements of GABA levels in human brain in vivo. Proc Nat Acad Sci USA 90:5662–5666PubMedGoogle Scholar
  188. 188.
    Bogner W, Gruber S, Doelken M, Stadlbauer A, Ganslandt O, Boettcher U, Trattnig S, Doerfler A, Stefan H, Hammen T (2010) In vivo quantification of intracerebral GABA by single-voxel (1)H-MRS-How reproducible are the results? Eur J Radiol 73:526–531PubMedGoogle Scholar
  189. 189.
    O’Gorman RL, Michels L, Edden RA, Murdoch JB, Martin E (2011) In vivo detection of GABA and glutamate with MEGA–PRESS: reproducibility and gender effects. J Magn Reson Imag 33:1262–1267Google Scholar
  190. 190.
    McLean MA, Busza AL, Wald LL, Simister RJ, Barker GJ, Williams SR (2002) In vivo GABA+ measurement at 1.5 T using a PRESS-localized double quantum filter. Magn Reson Med 48:233–241PubMedGoogle Scholar
  191. 191.
    Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R (1998) Simultaneous in vivo spectral editing and water suppression. NMR Biomed 11:266–272PubMedGoogle Scholar
  192. 192.
    Napolitano A, Kockenberger W, Auer DP (2013) Reliable gamma aminobutyric acid measurement using optimised PRESS at 3T. Magn Reson Med 69:1523–1528Google Scholar
  193. 193.
    Thomas MA, Hattori N, Umeda M, Sawada T, Naruse S (2003) Evaluation of two-dimensional L-COSY and PRESS using a 3T MRI scanner: from phantoms to human brain in vivo. NMR Biomed 16:245–251PubMedGoogle Scholar
  194. 194.
    Thomas MA, Yue K, Binesh N, Davanzo P, Kumar A, Siegel B, Frye M, Curran J, Lufkin R, Martin P, Guze B (2001) Localised two-dimensional shift correlated MR spectroscopy of human brain. Magn Reson Med 46:58–67PubMedGoogle Scholar
  195. 195.
    Choi CH, Coupland NJ, Hanstock CC, Ogilvie CJ, Higgins ACM, Gheorghiu D, Allen PS (2005) Brain gamma-aminobutyric acid measurement by proton double-quantum filtering with selective J rewinding. Magn Reson Med 54:272–279PubMedGoogle Scholar
  196. 196.
    Choi IY, Lee SP, Merkle H, Shen J (2006) In vivo detection of gray and white matter differences in GABA concentration in the human brain. Neuroimage 33:85–93PubMedGoogle Scholar
  197. 197.
    Evans CJ, McGonigle DJ, Edden RAE (2010) Diurnal stability of gamma-aminobutyric acid concentration in visual and sensorimotor cortex. J Magn Reson Imag 31:204–209Google Scholar
  198. 198.
    Gao F, Edden RA, Li M, Puts NA, Wang G, Liu C, Zhao B, Wang H, Bai X, Zhao C, Wang X, Barker PB (2013) Edited magnetic resonance spectroscopy detects an age-related decline in brain GABA levels. Neuroimage 78:75–82PubMedGoogle Scholar
  199. 199.
    Patel AB, Rothman DL, Cline GW, Behar KL (2001) Glutamine is the major precursor for GABA synthesis in rat neocortex in vivo following acute GABA-transaminase inhibition. Brain Res 919:207–220PubMedGoogle Scholar
  200. 200.
    Paulsen RE, Odden E, Fonnum F (1988) Importance of glutamine for gamma-aminobutyric acid synthesis in rat neostriatum in vivo. J Neurochem 13:637–641Google Scholar
  201. 201.
    Rae C, Hare N, Bubb WA, McEwan SR, Bröer A, McQuillan JA, Balcar VJ, Conigrave AD, Bröer S (2003) Inhibition of glutamine transport depletes glutamate and GABA neurotransmitter pools: further evidence for metabolic compartmentation. J Neurochem 85:503–514PubMedGoogle Scholar
  202. 202.
    Tapia R, González RM (1978) Glutamine and glutamate as precursors of the releasable pool of GABA in brain cortex slices. Neurosci Lett 10:165–169PubMedGoogle Scholar
  203. 203.
    Jackson MC, Scollard DM, Mack RJ, Lenney JF (1994) Localization of a novel pathway for the liberation of GABA in the human CNS. Brain Res Bull 33:379–385PubMedGoogle Scholar
  204. 204.
    Seiler N (2004) Catabolism of polyamines. Amino Acid 26:217–233Google Scholar
  205. 205.
    Heja L, Nyitrai G, Kekesi O, Dobolyi A, Szabo P, Fiath R, Ulbert I, Pal-Szenthe B, Palkovits M,Kardos J (2012) Astrocytes convert network excitation to tonic inhibition of neurons. Bmc Biol 10:26Google Scholar
  206. 206.
    Dericioglu N, Garganta CL, Petroff OA, Mendelsohn D, Williamson A (2008) Blockade of GABA synthesis only affects neural excitability under activated conditions in rat hippocampal slices. Neurochem Int 53:22–32PubMedCentralPubMedGoogle Scholar
  207. 207.
    Hanstock CC, Coupland NJ, Allen PS (2002) GABA X-2 multiplet measured pre- and post administration of vigabatrin in human brain. Magn Reson Med 48:617–623PubMedGoogle Scholar
  208. 208.
    Rae C, Nasrallah FA, Griffin JL, Balcar VJ (2009) Now I know my ABC. A systems neurochemistry and functional metabolomic approach to understanding the GABAergic system. J Neurochem 109(Suppl 1):109–116PubMedGoogle Scholar
  209. 209.
    Bak LK, Schousboe A, Waagepetersen HS (2006) The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 98:641–653PubMedGoogle Scholar
  210. 210.
    Nasrallah F, Griffin JL, Balcar VJ, Rae C (2009) Understanding your inhibitions. Effects of GABA and GABAA receptors on brain cortical metabolism. J Neurochem 108:57–71PubMedGoogle Scholar
  211. 211.
    Nasrallah F, Griffin JL, Balcar VJ, Rae C (2007) Understanding your inhibitions. Modulation of brain cortical metabolism by GABA-B receptors. J Cereb Blood Flow Metab 27:1510–1520PubMedGoogle Scholar
  212. 212.
    Möhler H (2006) GABAA receptor diversity and pharmacology. Cell Tissue Res 326:505–516PubMedGoogle Scholar
  213. 213.
    Petroff OAC, Behar KL, Mattson RH, Rothman DL (1996) Human brain gamma-aminobutyric acid levels and seizure control following initiation of vigabatrin therapy. J Neurochem 67:2399–2404PubMedGoogle Scholar
  214. 214.
    Cavelier P, Hamann V, Rossi D, Mobbs P, Attwell D (2005) Tonic excitation and inhibition of neurons: ambient transmitter sources and computational consequences. Prog Biophys Mol Biol 87:3–16PubMedGoogle Scholar
  215. 215.
    Schousboe A (2000) Pharmacological and functional characterisation of astrocytic GABA transport: a short review. Neurochem Res 25:1241–1244PubMedGoogle Scholar
  216. 216.
    Bolvig T, Larsson OM, Pickering DS, Nelson N, Falch E, Krogsgaard-Larsen P, Schousboe A (1999) Action of bicyclic isoxazole GABA analogues on GABA transporters and its relation to anticonvulsant activity. Eur J Pharmacol 375:367–374PubMedGoogle Scholar
  217. 217.
    Richerson GB, Wu Y (2003) Dynamic equilibrium of neurotransmitter transporters: not just for reuptake anymore. J Neurophysiol 90:1363–1374PubMedGoogle Scholar
  218. 218.
    Yasumi M, Sato K, Shimada S, Nishimura M, Tohyama M (1997) Regional distribution of GABA transporter 1 (GAT1) mRNA in the rat brain: comparison with glutamic acid decarboxylase(67)(GAD(67))mRNA localization. Mol Brain Res 44:205–218PubMedGoogle Scholar
  219. 219.
    Bernstein EM, Quick MW (1999) Regulation of γ-aminobutyric acid (GABA) transporters by extracellular GABA. J Biol Chem 274:889–895PubMedGoogle Scholar
  220. 220.
    Jackson MF, Esplin B, Capek R (2000) Reversal of the activity-dependent suppression of GABA-mediated inhibition in hippocampal slices from gamma-vinyl GABA (vigabatrin)-pretreated rats. Neuropharmacol 39:65–74Google Scholar
  221. 221.
    Wu Y, Wang W, Richerson GB (2003) Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release. J Neurophysiol 89:2021–2034PubMedGoogle Scholar
  222. 222.
    Wu YM, Wang WG, Diez-Sampedro A, Richerson GB (2007) Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1. Neuron 56:851–865PubMedCentralPubMedGoogle Scholar
  223. 223.
    Puts NAJ, Edden RAE (2012) In vivo magnetic resonance spectroscopy of GABA: a methodological review. Prog NMR Spect 60:29–41Google Scholar
  224. 224.
    Floyer-Lea A, Wylezinska M, Kincses T, Matthews PM (2005) Rapid modulation of GABA concentration in human sensorimotor cortex during motor learning. J Neurophysiol 95:1639–1644PubMedGoogle Scholar
  225. 225.
    Sumner P, Edden RAE, Bompas A, Evans CJ, Singh KD (2010) More GABA, less distraction: a neurochemical predictor of motor decision speed. Nat Neurosci 13:825–827PubMedGoogle Scholar
  226. 226.
    Boy F, Evans CJ, Edden RAE, Singh KD, Husain M, Sumner P (2010) Individual differences in subconscious motor control predicted by GABA concentration in SMA. Curr Biol 20:1779–1785PubMedCentralPubMedGoogle Scholar
  227. 227.
    Henderson LA, Peck CC, Petersen ET, Rae CD, Youssef AM, Reeves JM, Wilcox SL, Akhter R, Murray GM, Gustin SM (2013) Chronic pain: lost inhibition? J Neurosci 33:7574–7582PubMedGoogle Scholar
  228. 228.
    Edden RAE, Muthukumaraswamy SD, Freeman TCA, Singh KD (2009) Orientation discrimination performance is predicted by GABA concentration and gamma oscillation frequency in human primary visual cortex. J Neurosci 29:15721–15726PubMedGoogle Scholar
  229. 229.
    Marenco S, Savostyanova AA, van der Veen JW, Geramita M, Stern A, Barnett AS, Kolachana B, Radulescu E, Zhang FY, Callicott JH, Straub RE, Shen J, Weinberger DR (2010) Genetic Modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT. Neuropsychpharmacol 35:1708–1717Google Scholar
  230. 230.
    Northoff G, Walter M, Schulte RF, Beck J, Dydak U, Henning A, Boeker H, Grimm S, Boesiger P (2007) GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI. Nat Neurosci 10:1515–1517PubMedGoogle Scholar
  231. 231.
    Donahue MJ, Near J, Blicher JU, Jezzard P (2010) Baseline GABA concentration and fMRI response. Neuroimage 53:392–398PubMedGoogle Scholar
  232. 232.
    Chatton JY, Pellerin L, Magistretti PJ (2003) GABA uptake into astrocytes is not associated with significant metabolic cost: implications for brain imaging of inhibitory transmission. Proc Natl Acad Sci USA 100:12456–12461PubMedGoogle Scholar
  233. 233.
    Ackermann RF, Finch DM, Babb TL, Engel J (1984) Increased glucose-metabolism during long-duration recurrent inhibition of hippocampal pyramidal cells. J Neurosci 4:251–264PubMedGoogle Scholar
  234. 234.
    Palacios JM, Kuhar MJ, Rapoport SI, London ED (1982) Effects of γ-aminobutyric acid agonist and antagonist drugs on local cerebral glucose utilization. J Neurosci 2:853–860PubMedGoogle Scholar
  235. 235.
    Peyron R, Le Bars D, Cinotti L, Garcia-Larrea L, Galy G, Landais P, Millet P, Lavenne F, Froment JC, Krogsgaard-Larsen P (1994) Effects of GABAA receptors activation on brain glucose metabolism in normal subjects and temporal lobe epilepsy (TLE) patients. A positron emission tomography (PET) study. Part 1: brain glucose metabolism is increased after GABAA receptors activation. Epilepsy Res 19:45–54PubMedGoogle Scholar
  236. 236.
    Roland PE, Friberg L (1988) The effect of the GABA-A agonist THIP on regional cortical blood flow in humans. A new test of hemispheric dominance. J Cereb Blood Flow Metab 8:314–323PubMedGoogle Scholar
  237. 237.
    Tagamets MA, Horwitz B (2001) Interpreting PET and fMRI measures of functional neural activity: the effects of synaptic inhibition on cortical activation in human imaging studies. Brain Res Bull 54:267–273PubMedGoogle Scholar
  238. 238.
    Gaetz W, Edgar JC, Wang DJ, Roberts TPL (2011) Relating MEG measured motor cortical oscillations to resting gamma-aminobutyric acid (GABA) concentration. Neuroimage 55:616–621PubMedCentralPubMedGoogle Scholar
  239. 239.
    Traub RD, Cunningham MO, Gloveli T, LeBeau FEN, Bibbig A, Buhl EH, Whittington MA (2003) GABA-enhanced collective behavior in neuronal axons underlies persistent gamma-frequency oscillations. Proc Natl Acad Sci USA 100:11047–11052PubMedGoogle Scholar
  240. 240.
    Nasrallah FA, Balcar VJ, Rae CD (2011) Activity dependent GABA release controls brain cortical tissue slice metabolism. J Neurosci Res 89:1935–1945PubMedGoogle Scholar
  241. 241.
    Stagg CJ, Bestmann S, Constantinescu AO, Moreno LM, Allman C, Mekle R, Woolrich M, Near J, Johansen-Berg H, Rothwell JC (2011) Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex. J Physiol-Lond 589:5845–5855PubMedGoogle Scholar
  242. 242.
    Michaelis T, Merboldt K-D, Hänicke W, Gyngell ML, Bruhn H, Frahm J (1991) On the identification of cerebral metabolites in localised 1H NMR spectra of human brain in vivo. NMR Biomed 4:90–98PubMedGoogle Scholar
  243. 243.
    Marjanska M, Henry PG, Bolan PJ, Vaughan B, Seaquist ER, Gruetter R, Ugurbil K, Garwood M (2005) Uncovering hidden in vivo resonances using editing based on localized TOCSY. Magn Reson Med 53:783–789PubMedCentralPubMedGoogle Scholar
  244. 244.
    Keltner JR, Wald LL, Ledden PJ, Chen YCI, Matthews RT, Kuestermann E, Baker JR, Rosen BR, Jenkins BG (1998) Localized double-quantum filter for the in vivo detection of brain glucose. Magn Reson Med 39:651–656PubMedGoogle Scholar
  245. 245.
    de Graaf RA, Dijkhuizen RM, Biessels GJ, Braun KPJ, Nicolay K (2000) In vivo glucose detection by homonuclear spectral editing. Magn Reson Med 43:621–626PubMedGoogle Scholar
  246. 246.
    Mitrakou A, Ryan C, Veneman T, Mokan M, Jenssen T, Kiss I, Durrant J, Cryer P, Gerich J (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260:E67–E74PubMedGoogle Scholar
  247. 247.
    Bachelard HS, Cox DWG, Drower J (1984) Sensitivity of guinea-pig hippocampal granule cell field potentials to hexoses in vitro: an effect on cell excitability? J Physiol 352:91–102PubMedGoogle Scholar
  248. 248.
    Mata M, Fink DJ, Gainer H, Smith CB, Davidsen L, Savaki H, Schwartz WJ, Sokoloff L (1980) Activity-dependent energy metabolism in rat posterior pituitary primarily reflects sodium pump activity. J Neurochem 34:213–215PubMedGoogle Scholar
  249. 249.
    Vannucci SJ, Maher F, Simpson IA (1997) Glucose tranporter proteins in brain: delivery of glucose to neurons and glia. Glia 21:2–21PubMedGoogle Scholar
  250. 250.
    Morgello S, Uson RR, Schwartz EJ, Haber RS (1995) The human blood-brain barrier glucose transporter (GLUT 1) is a glucose transporter of gray matter astrocytes. Glia 14:43–54PubMedGoogle Scholar
  251. 251.
    Zeller K, Rahner-Welsch S, Kuschinsky W (1997) Distribution of GLUT1 glucose tranporters in different brain structures compared to glucose utilization and capillary density of adult rat brains. J Cereb Blood Flow Metab 17:204–209PubMedGoogle Scholar
  252. 252.
    Vannucci SJ, Clark RR, Koehler-Stec E, Li K, Smith CB, Davies P, Maher F, Simpson IA (1998) Glucose tranporter expression in brain: relationship to cerebral glucose utilisation. Dev Neurosci 20:369–379PubMedGoogle Scholar
  253. 253.
    Bachelard HS, Daniel PM, Love ER, Pratt OE (1973) The transport of glucose into the brain of the rat in vivo. Proc R Soc Lond B 183:71–82PubMedGoogle Scholar
  254. 254.
    Nagamatsu S, Sawa H, Kamada K, Nakamichi Y, Yoshimoto K, Hoshino T (1993) Neuron-specific glucose transporter (NSGT): CNS distribution of GLUT3 rat glucose transporter (RGT3) in rat central neurons. FEBS Lett 334:289–295PubMedGoogle Scholar
  255. 255.
    Maher F, Davies-Hill TM, Simpson IA (1996) Substrate specificity and kinetic parameters of GLUT3 in rat cerebellar granule neurons. Biochem J 315:827–831PubMedGoogle Scholar
  256. 256.
    Lund-Andersen H (1979) Transport of glucose from blood to brain. Physiol Rev 59:305–352PubMedGoogle Scholar
  257. 257.
    Pfeuffer J, Tkác I, Gruetter R (2000) Extracellular-intracellular distribution of glucose and lactate in the rat brain assessed noninvasively by diffusion-weighted 1H nuclear magnetic resonance spectroscopy in vivo. J Cereb Blood Flow Metab 20:736–746PubMedGoogle Scholar
  258. 258.
    Silver IA, Erecinska M (1998) Glucose-induced intracellular ion changes in sugar-sensitive hypothalamic neurons. J Neurophysiol 79:1733–1745PubMedGoogle Scholar
  259. 259.
    Nicholson C, Syková E (1998) Extracellular space structure revealed by diffusion analysis. Trends Neurosci 21:207–215PubMedGoogle Scholar
  260. 260.
    de Graaf RA, Pan JW, Telang F, Lee JH, Brown P, Novotny EJ, Hetherington HP, Rothman D (2001) Differentiation of glucose transport in human brain gray and white matter. J Cereb Blood Flow Metab 21:483–492PubMedGoogle Scholar
  261. 261.
    Merboldt K-D, Bruhn H, Hänicke W, Michaelis T, Frahm J (1992) Decrease of glucose in the human visual cortex during photic stimulation. Magn Reson Med 25:187–194PubMedGoogle Scholar
  262. 262.
    Erecinska M, Silver IA (1994) Ions and energy in mammalian brain. Prog Neurobiol 43:37–71PubMedGoogle Scholar
  263. 263.
    Dienel GA (2013) Fuelling and imaging brain activation. ASN Neuro 4:267–321Google Scholar
  264. 264.
    Cataldo AM, Broadwell RD (1986) Cytochemical identification of cerebral glycogen and glucose-6-phosphatase activity under normal and experimental conditions. II. Choroid plexus and ependymal epithelia, endothelia and pericytes. J Neurocytol 15:511–524PubMedGoogle Scholar
  265. 265.
    Bhattacharya SB, Datta AG (1993) Is brain a gluconeogenic organ? Mol Cell Biochem 125:51–57PubMedGoogle Scholar
  266. 266.
    Dringen R, Schmoll D, Cesar M, Hamprecht B (1993) Incorporation of radioactivity from C-14 lactate into the glycogen of cultured mouse astroglial cells—evidence for gluconeogenesis in brain cells. Biol Chem Hoppe-Seyler 374:343–347PubMedGoogle Scholar
  267. 267.
    Griffin JL, Rae C, Radda GK, Matthews PM (1999) Delayed labelling of brain glutamate after an intra-arterial [13C]glucose bolus: evidence for aerobic metabolism of guinea pig brain glycogen store. Biochim Biophys Acta 1450:297–307PubMedGoogle Scholar
  268. 268.
    Swanson R (1992) Physiological coupling of glial glycogen metabolism to neuronal activity in brain. Can J Physiol Pharmacol 70:S138–S144PubMedGoogle Scholar
  269. 269.
    Xu J, Song D, Xue Z, Gu L, Hertz L, Peng L (2013) Requirement of glycogenolysis for uptake of increased extracellular K+ in astrocytes: potential implications for K+ homeostasis and glycogen usage in brain. Neurochem Res 38:472–485PubMedGoogle Scholar
  270. 270.
    Nelson T, Lucignani G, Atlas S, Crane A, Dienel G, Sokoloff L (1985) Reexamination of glucose-6-phosphatase activity in the brain in vivo: no evidence for a futile cycle. Science 229:60–62PubMedGoogle Scholar
  271. 271.
    Vilchez D, Ros S, Cifuentes D, Pujadas L, Valles J, Garcia-Fojeda B, Criado-Garcia O, Fernandez-Sanchez E, Medrano-Fernandez I, Dominguez J, Garcia-Rocha M, Soriano E, De Cordoba SR, Guinovart JJ (2007) Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci 10:1407–1413PubMedGoogle Scholar
  272. 272.
    Choi CH, Coupland NJ, Bhardwaj PP, Kalra S, Casault CA, Reid K, Allen PS (2006) T-2 measurement and quantification of glutamate in human brain in vivo. Magn Reson Med 56:971–977PubMedGoogle Scholar
  273. 273.
    Jardetzky O, Jardetzky CD (1958) Proton magnetic resonance spectra of amino acids. J Biol Chem 233:383–387PubMedGoogle Scholar
  274. 274.
    Field LD, Sternhell S, Kalman JR (2008) Organic structures from spectra, 4th edn. Wiley, ChichesterGoogle Scholar
  275. 275.
    Schubert F, Gallinat J, Seifert F, Rinneberg H (2004) Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla. Neuroimage 21:1762–1771PubMedGoogle Scholar
  276. 276.
    Wijtenburg SA, Knight-Scott J (2011) Very short echo time improves the precision of glutamate detection at 3T in (1)H magnetic resonance spectroscopy. J Magn Reson Imag 34:645–652Google Scholar
  277. 277.
    Snyder J, Wilman A (2010) Field strength dependence of PRESS timings for simultaneous detection of glutamate and glutamine from 1.5 to 7 T. J Magn Reson 203:66–72PubMedGoogle Scholar
  278. 278.
    Hancu I (2009) Optimized glutamate detection at 3T. J Magn Reson Imag 30:1155–1162Google Scholar
  279. 279.
    Mullins PG, Chen H, Xu J, Caprihan A, Gasparovic C (2008) Comparative reliability of proton spectroscopy techniques designed to improve detection of J-coupled metabolites. Magn Reson Med 60:964–969PubMedGoogle Scholar
  280. 280.
    Provencher SW (1993) Estimation of metabolite concentrations from localised in vivo proton NMR spectra. Magn Reson Med 30:672–679PubMedGoogle Scholar
  281. 281.
    Naressi A, Couturier C, Devos JM, Janssen M, Mangeat C, de Beer R, Graveron-Demilly D (2001) Java-based graphical user interface for the MRUI quantitation package. Magma 12:141–152PubMedGoogle Scholar
  282. 282.
    Tkac I, Oz G, Adriany G, Ugurbil K, Gruetter R (2009) In vivo H-1 NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T. Magn Reson Med 62:868–879PubMedCentralPubMedGoogle Scholar
  283. 283.
    Bennett MR, Balcar VJ (1999) Forty years of amino acid transmission in the brain. Neurochem Int 35:269–280PubMedGoogle Scholar
  284. 284.
    Fonnum F (1984) Glutamate—a neurotransmitter in mammalian brain. J Neurochem 42:1–11PubMedGoogle Scholar
  285. 285.
    Yang JH, Xu S, Shen J (2009) Fast isotopic exchange between mitochondria and cytosol in brain revealed by relayed C-13 magnetization transfer spectroscopy. J Cereb Blood Flow Metab 29:661–669PubMedCentralPubMedGoogle Scholar
  286. 286.
    Yudkoff M (1997) Brain metabolism of branched-chain amino acids. Glia 21:92–98PubMedGoogle Scholar
  287. 287.
    Berl S, Lajtha A, Waelsch H (1961) Amino acid and protein metabolism-VI Cerebral compartments of glutamic acid metabolism. J Neurochem 7:186–197Google Scholar
  288. 288.
    Shank RP, Leo GC, Zielke HR (1993) Cerebral metabolic compartmentation as revealed by nuclear magnetic resonance analysis of D-[1-13C]glucose metabolism. J Neurochem 61:315–323PubMedGoogle Scholar
  289. 289.
    Kreft M, Bak LK, Waagepetersen HS, Schousboe A (2012) Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation. Asn Neuro 4(3):e00086Google Scholar
  290. 290.
    Bordi F, Ugolini A (1999) Group I metabotropic glutamate receptors: implications for brain diseases. Prog Neurobiol 59:55–79PubMedGoogle Scholar
  291. 291.
    Kew JNC, Kemp JA (2005) Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacol 179:4–29Google Scholar
  292. 292.
    Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 35:1–105Google Scholar
  293. 293.
    Albrecht P, Lewerenz J, Dittmer S, Noack R, Maher P, Methner A (2010) Mechanisms of oxidative glutamate toxicity: the glutamate/cystine antiporter system x(c)(−) as a neuroprotective drug target. CNS Neurol Disord-Drug Targets 9:373–382PubMedGoogle Scholar
  294. 294.
    Kalivas PW (2009) The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 10:561–572PubMedGoogle Scholar
  295. 295.
    Koga M, Serritella AV, Messmer MM, Hayashi-Takagi A, Hester LD, Snyder SH, Sawa A, Sedlak TW (2011) Glutathione is a physiologic reservoir of neuronal glutamate. Biochem Biophys Res Commun 409:596–602PubMedGoogle Scholar
  296. 296.
    Choi DW (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369–379PubMedGoogle Scholar
  297. 297.
    Dienel GA (2013) Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis? Neurochem Int 63:244–258PubMedGoogle Scholar
  298. 298.
    Lin Y, Stephenson MC, Xin L, Napolitano A, Morris PG (2012) Investigating the metabolic changes due to visual stimulation using functional proton magnetic resonance spectroscopy at 7 T. J Cereb Blood Flow Metab 32:1484–1495PubMedGoogle Scholar
  299. 299.
    Mangia S, Giove F, DiNuzzo M (2012) Metabolic pathways and activity-dependent modulation of glutamate concentration in the human brain. Neurochem Res 37:2554–2561PubMedCentralPubMedGoogle Scholar
  300. 300.
    Schaller B, Mekle R, Xin LJ, Kunz N, Gruetter R (2013) Net increase of lactate and glutamate concentration in activated human visual cortex detected with magnetic resonance spectroscopy at 7 Tesla. J Neurosci Res 91:1076–1083PubMedGoogle Scholar
  301. 301.
    Sibson NR, Dhankhar A, Mason GF, Rothman DL, Behar KL, Shulman RG (1998) Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proc Natl Acad Sci USA 95:316–321PubMedGoogle Scholar
  302. 302.
    Perry TL, Hansen S, Berry K, Mok C, Lesk D (1971) Free amino acids and related compounds in biopsies of human brain. J Neurochem 18:521–528PubMedGoogle Scholar
  303. 303.
    Oz G, Tkac I (2011) Short-echo, single-shot, full-intensity proton magnetic resonance spectroscopy for neurochemical profiling at 4 T: validation in the cerebellum and brainstem. Magn Reson Med 65:901–910PubMedGoogle Scholar
  304. 304.
    Kassem MNE, Bartha R (2003) Quantitative proton short-echo-time LASER spectroscopy of normal human white matter and hippocampus at 4 Tesla incorporating macromolecule subtraction. Magn Reson Med 49:918–927PubMedGoogle Scholar
  305. 305.
    Hancu I, Port J (2011) The case of the missing glutamine. NMR Biomed 24:529–535PubMedGoogle Scholar
  306. 306.
    Prescot A, Richards T, Dager SR, Choi C, Renshaw PF Phase-adjusted echo time (PATE)-averaging 1H MRS: application for improved glutamine quantification at 2.89T. NMR Biomed 25:1245–1252Google Scholar
  307. 307.
    Rae C, Geng G, Williams SR (2012) Going for glutamine: evaluation of asymmetric PRESS approaches. Proc Int Soc Magn Reson Med 20:1753Google Scholar
  308. 308.
    Martinez-Hernandez A, Bell KP, Norenberg MD (1977) Glutamine synthetase—glial localization in brain. Science 195:1356–1358PubMedGoogle Scholar
  309. 309.
    Fernandes SP, Dringen R, Lawen A, Robinson SR (2010) Neurones express glutamine synthetase when deprived of glutamine or interaction with astrocytes. J Neurochem 114:1527–1536PubMedGoogle Scholar
  310. 310.
    Kanamori K, Ross BD, Chung JC, Kuo EL (1996) Severity of hyperammonemic encephalopathy correlates with brain ammonia level and saturation of glutamine synthetase in vivo. J Neurochem 67:1584–1594PubMedGoogle Scholar
  311. 311.
    Peng L, Hertz L, Huang R, Sonnewald U, Petersen SB, Westergaard N, Larsson OM, Schousboe A (1993) Utilization of glutamine and of TCA cycle constituents as precursors for transmitter glutamate and GABA. Dev Neurosci 15:367–377PubMedGoogle Scholar
  312. 312.
    Lieth E, LaNoue KF, Berkich DA, Xu B, Ratz M, Taylor C, Hutson SM (2001) Nitrogen shuttling between neurons and glial cells during glutamate synthesis. J Neurochem 76:1712–1723PubMedGoogle Scholar
  313. 313.
    Sibson NR, Mason GF, Shen J, Cline GW, Herskovits AZ, Wall JEM, Behar KL, Rothman DL, Shulman RG (2001) In vivo 13C NMR measurement of neurotransmitter glutamate cycling, anaplerosis and TCA cycle flux in rat brain during [2-13C]glucose infusion. J Neurochem 76:975–989PubMedGoogle Scholar
  314. 314.
    Badar-Goffer R, Bachelard H, Morris P (1990) Cerebral metabolism of acetate and glucose studied by 13C NMR spectroscopy. Biochem J 266:133–139PubMedGoogle Scholar
  315. 315.
    Bröer S, Brookes N (2001) Transfer of glutamine between astrocytes and neurons. J Neurochem 77:705–719PubMedGoogle Scholar
  316. 316.
    Deitmer JW, Bröer A, Bröer S (2003) Glutamine efflux from astrocytes is mediated by multiple pathways. J Neurochem 87:127–135PubMedGoogle Scholar
  317. 317.
    Walter M, Henning A, Grimm S, Schulte RF, Beck J, Dydak U, Schnepf B, Boeker H, Boesiger P, Northoff G (2009) The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. Arch Gen Psychiatr 66:478–486PubMedGoogle Scholar
  318. 318.
    Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E, Barrow R, Yeo R, Lauriello J, Brooks WM (2005) Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatr 162:394–396PubMedGoogle Scholar
  319. 319.
    Moore CM, Wardrop M, Frederick BD, Renshaw PF (2006) Topiramate raises anterior cingulate cortex glutamine levels in healthy men; a 4.0 T magnetic resonance spectroscopy study. Psychopharmacol 188:236–243Google Scholar
  320. 320.
    Henry ME, Jensen JE, Licata SC, Ravichandran C, Butman ML, Shanahan M, Lauriat TL, Renshaw PF (2010) The acute and late CNS glutamine response to benzodiazepine challenge: a pilot pharmacokinetic study using proton magnetic resonance spectroscopy. Psychiatr Res Neuroimag 184:171–176Google Scholar
  321. 321.
    Petroff OAC, Pleban LA, Spencer DD (1995) Symbiosis between in vivo and in vitro NMR spectroscopy—the creatine, N-acetylaspartate, glutamate and GABA content of the epileptic human brain. Magn Reson Imag 13:1197–1211Google Scholar
  322. 322.
    Zhang NY, Laake J, Nagelhus E, Storm-Mathisen J, Ottersen OP (1991) Distribution of glutamine-like immunoreactivity in the cerebellum of rat and baboon (Papio anubis) with reference to the issue of metabolic compartmentation. Anat Embryol 184:213–223PubMedGoogle Scholar
  323. 323.
    Hertz L, Dringen R, Schousboe A, Robinson SR (1999) Astrocytes: glutamate producers for neurons. J Neurosci Res 57:417–428PubMedGoogle Scholar
  324. 324.
    Terpstra M, Henry PG, Gruetter R (2003) Measurement of reduced glutathione (GSH) in human brain using LCmodel analysis of difference-edited spectra. Magn Reson Med 50:19–23PubMedGoogle Scholar
  325. 325.
    Kaiser LG, Marjanska M, Matson GB, Iltis I, Bush SD, Soher BJ, Mueller S, Young K (2010) (1)H MRS detection of glycine residue of reduced glutathione in vivo. J Magn Reson 202:259–266PubMedCentralPubMedGoogle Scholar
  326. 326.
    Terpstra M, Vaughan TJ, Ugurbil K, Lim KO, Schulz SC, Gruetter R (2005) Validation of glutathione quantitation from STEAM spectra against edited H-1 NMR spectroscopy at 4T: application to schizophrenia. Magn Reson Mater Phys, Biol Med 18:276–282Google Scholar
  327. 327.
    Maher P (2005) The effects of stress and aging on glutathione metabolism. Age Res Rev 4:288–314Google Scholar
  328. 328.
    Satoh T, Yoshioka Y (2006) Contribution of reduced and oxidized glutathione to signals detected by magnetic resonance spectroscopy as indicators of local brain redox state. Neurosci Res 55:34–39PubMedGoogle Scholar
  329. 329.
    Ballatori N, Krance SM, Notenboom S, Shi SJ, Tieu K, Hammond CL (2009) Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem 390:191–214PubMedCentralPubMedGoogle Scholar
  330. 330.
    Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radical Biol Med 30:1191–1212Google Scholar
  331. 331.
    Rice ME, RussoMenna I (1998) Differential compartmentalization of brain ascorbate and glutathione between neurons and glia. Neuroscience 82:1213–1223PubMedGoogle Scholar
  332. 332.
    Keelan J, Allen NJ, Antcliffe D, Pal S, Duchen MR (2001) Quantitative imaging of glutathione in hippocampal neurons and glia in culture using monochlorobimane. J Neurosci Res 66:873–884PubMedGoogle Scholar
  333. 333.
    Langeveld CH, Schepens E, Jongenelen CAM, Stoof JC, Hjelle OP, Ottersen OP, Drukarch B (1996) Presence of glutathione immunoreactivity in cultured neurones and astrocytes. NeuroRep 7:1833–1836Google Scholar
  334. 334.
    Makar TK, Nedergaard M, Preuss A, Gelbard AS, Perumal AS, Cooper AJL (1994) Vitamin-E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons—evidence that astrocytes play an important role in antioxidative processes in the brain. J Neurochem 62:45–53PubMedGoogle Scholar
  335. 335.
    Srinivasan R, Ratiney H, Hammond-Rosenbluth KE, Pelletier D, Nelson SJ (2010) MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an application to multiple sclerosis. Magn Reson Imag 28:163–170Google Scholar
  336. 336.
    Harish G, Venkateshappa C, Mahadevan A, Pruthi N, Bharath MMS, Shankar SK (2011) Glutathione metabolism is modulated by postmortem interval, gender difference and agonal state in postmortem human brains. Neurochem Int 59:1029–1042PubMedGoogle Scholar
  337. 337.
    Meister A, Anderson ME (1983) Glutathione. Ann Rev Biochem 52:711–760PubMedGoogle Scholar
  338. 338.
    Meister A (1974) Glutathione—metabolism and function via gamma-glutamyl cycle. Life Science 15:177–190Google Scholar
  339. 339.
    Anderson ME (1998) Glutathione: an overview of biosynthesis and modulation. Chem Biol Interact 112:1–14Google Scholar
  340. 340.
    Janaky R, Varga V, Hermann A, Saransaari P, Oja SS (2000) Mechanisms of l-cysteine neurotoxicity. Neurochem Res 25:1397–1405PubMedGoogle Scholar
  341. 341.
    Vitvitsky V, Thomas M, Ghorpade A, Gendelman HE, Banerjee R (2006) A functional transsulfuration pathway in the brain links to glutathione homeostasis. J Biol Chem 281:35785–35793PubMedGoogle Scholar
  342. 342.
    Kranich O, Dringen R, Sandberg M, Hamprecht B (1998) Utilization of cysteine and cysteine precursors for the synthesis of glutathione in astroglial cultures: preference for cystine. Glia 22:11–18PubMedGoogle Scholar
  343. 343.
    Wang XF, Cynader MS (2000) Astrocytes provide cysteine to neurons by releasing glutathione. J Neurochem 74:1434–1442PubMedGoogle Scholar
  344. 344.
    Dringen R, Pfeiffer B, Hamprecht B (1999) Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci 19:562–569PubMedGoogle Scholar
  345. 345.
    Sagara J, Miura K, Bannai S (1993) Maintenance of neuronal glutathione by glial-cells. J Neurochem 61:1672–1676PubMedGoogle Scholar
  346. 346.
    O’Brien PJ, Siraki AG, Shangari N (2005) Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health. Crit Rev Toxicol 35:609–662PubMedGoogle Scholar
  347. 347.
    Heales SJR, Davies SEC, Bates TE, Clark JB (1995) Depletion of brain glutathione is accompanied by impaired mitochondrial-function and decreased N-acetyl aspartate concentration. Neurochem Res 20:31–38PubMedGoogle Scholar
  348. 348.
    Holub BJ (1986) Metabolism and function of myo-inositol and inositol phospholipids. Annu Rev Nutr 6:563–597PubMedGoogle Scholar
  349. 349.
    Cerdan S, Parrilla R, Santoro J, Rico M (1985) 1H NMR detection of cerebral myo-inositol. FEBS Lett 187:167–172PubMedGoogle Scholar
  350. 350.
    Hancu I, Gillen R, Cowan J, Zimmerman EA (2011) Improved myo-inositol detection through Carr-Purcell PRESS: a tool for more sensitive mild cognitive impairment diagnosis. Magn Reson Med 65:1515–1521PubMedCentralPubMedGoogle Scholar
  351. 351.
    Minati L, Aquino D, Bruzzone MG, Erbetta A (2010) Quantitation of normal metabolite concentrations in six brain regions by in vivo 1H-MR spectroscopy. J Med Phys 35:154–163PubMedCentralPubMedGoogle Scholar
  352. 352.
    Haris M, Cai KJ, Singh A, Hariharan H, Reddy R (2011) In vivo mapping of brain myo-inositol. Neuroimage 54:2079–2085PubMedCentralPubMedGoogle Scholar
  353. 353.
    Fisher SK, Novak JE, Agranoff BW (2002) Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance. J Neurochem 82:736–754PubMedGoogle Scholar
  354. 354.
    Belmaker RH, Agam G, van Calker D, Richards MH, Kofman O (1998) Behavioural reversal of lithium effects by four inositol isomers correlates perfectly with biochemical effects on the PI cycle. Neuropsychpharmacol 19:220–232Google Scholar
  355. 355.
    Glanville NT, Byers DM, Cook HW, Spence MW, Palmer FBSC (1989) Differences in the metabolism of inositol and phosphoinositides by cultured cells of neuronal and glial origin. Biochim Biophys Acta 1004:169–179PubMedGoogle Scholar
  356. 356.
    Wiesinger H (1991) Myo-inositol transport in mouse astroglia-rich primary cultures. J Neurochem 56:1698–1704PubMedGoogle Scholar
  357. 357.
    Novak JE, Turner RS, Agranoff BW, Fisher SK (1999) Differentiated human NT2-N neurons possess a high intracellular content of myo-inositol. J Neurochem 72:1431–1440PubMedGoogle Scholar
  358. 358.
    Wong Y-HH, Kalmbach SJ, Hartmann BK, Sherman WR (1987) Immunohistochemical staining and enzyme activity measurements show myo-inositol-1-phosphate synthase to be localised in the vasculature of the brain. J Neurochem 48:1434–1442PubMedGoogle Scholar
  359. 359.
    Kim JP, Lentz MR, Westmoreland SV, Greco JB, Ratai EM, Halpern E, Lackner AA, Masliah E, Gonzalez RG (2005) Relationships between astrogliosis and H-1 MR spectroscopic measures of brain choline/creatine and myo-inositol/creatine in a primate model. Am J Neuroradiol 26:752–759PubMedGoogle Scholar
  360. 360.
    Vadnal R, Parthasarathy L, Parthasarathy R (1997) Role of inositol in the treatment of psychiatric disorders. CNS Drugs 7:6–16Google Scholar
  361. 361.
    Gani D, Downes CP, Batty I, Bramham J (1993) Lithium and myo-inositol homeostasis. Biochim Biophys Acta 1177:253–269PubMedGoogle Scholar
  362. 362.
    Futerman AH, Low MG, Ackerman KE, Sherman WR, Silman I (1985) Identification of covalently bound inositol in the hydrophobic membrane-anchoring domain of Torpedo acetylcholinesterase. Biochem Biophys Res Commun 129:312–317PubMedGoogle Scholar
  363. 363.
    Elmallakh RS, Li R (1993) Is the Na+–K+-ATPase the link between phosphoinositide metabolism and bipolar disorder. J Neuropsychiatr Clin Neurosci 5:361–368Google Scholar
  364. 364.
    Jones DR, Varela-Nieto I (1999) Diabetes and the role of inositol-containing lipids in insulin signaling. Mol Med 5:505–514PubMedCentralPubMedGoogle Scholar
  365. 365.
    Levine J, Chengappa KNR, Reddy R (1999) Acute myoinositol enhances swimming activity in goldfish. J Neural Transm 106:433–441PubMedGoogle Scholar
  366. 366.
    Fux M, Levine J, Aviv A, Belmaker RH (1996) Inositol treatment of obsessive-compulsive disorder. Am J Psychiatr 153:1219–1221PubMedGoogle Scholar
  367. 367.
    Strange K, Morrison R, Shrode L, Putnam R (1993) Mechanism and regulation of swelling-activated inositol efflux in brain glial cells. Am J Physiol 265:C244–C256PubMedGoogle Scholar
  368. 368.
    Häussinger D, Laubenberger J, Vom Dahl S, Ernst T, Bayer S, Langer M, Gerok W, Hennig J (1994) Proton magnetic resonance spectroscopy studies on human brain myo-inositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterol 107:1475–1480Google Scholar
  369. 369.
    Trachtman H, Futterweit S, Hammer E, Siegel TW, Oates P (1991) The role of polyols in cerebral cell volume regulation in hypernatremic and hyponatremic states. Life Science 49:677–688Google Scholar
  370. 370.
    Rumpel H, Lim WEH, Chang HM, Chan LL, Ho GL, Wong MC, Tan KP (2003) Is myo-inositol a measure of glial swelling after stroke? A magnetic resonance study. J Magn Reson Imag 17:11–19Google Scholar
  371. 371.
    Ashwal S, Holshouser B, Tong K, Serna T, Osterdock R, Gross M, Kido D (2004) Proton spectroscopy detected myoinositol in children with traumatic brain injury. Pediatr Res 56:630–638PubMedGoogle Scholar
  372. 372.
    Rango M, Cogiamanian F, Marceglia S, Barberis B, Arighi A, Biondetti P, Priori A (2008) Myoinositol content in the human brain is modified by transcranial direct current stimulation in a matter of minutes: a 1H-MRS study. Magn Reson Med 60:782–789PubMedGoogle Scholar
  373. 373.
    Spector R (1988) Myo-inositol transport through the blood brain barrier. Neurochemical Res 13:785–787Google Scholar
  374. 374.
    Levine J, Rapaport A, Lev L, Bersudsky Y, Kofman O, Belmaker RH, Shapiro J, Agam G (1993) Inositol treatment raises CSF inositol levels. Brain Res 627:168–170PubMedGoogle Scholar
  375. 375.
    Patishi Y, Lubrich B, Berger M, van Calker D, Kofman O, Belmaker RH (1996) Differential uptake of myo-inositol in vivo into rat brain areas. Eur Neuropsychopharmacol 6:73–75PubMedGoogle Scholar
  376. 376.
    Berry GT, Wu S, Buccafusca R, Ren J, Gonzales LW, Ballard PL, Golden JA, Stevens MJ, Greer JJ (2003) Loss of murine Na+/myo-inositol cotransporter leads to brain myo-inositol depletion and central apnea. J Biol Chem 278:18297–18302PubMedGoogle Scholar
  377. 377.
    Guo W, Shimada S, Tajiri H, Yamauchi A, Yamashita T, Okada S, Tohyama M (1997) Developmental regulation of Na+/myo-inositol cotransporter gene expression. Mol Brain Res 51:91–96PubMedGoogle Scholar
  378. 378.
    Battaglia FC, Meschia JN, Blechnew JN, Barron DH (1961) The free myo-inositol concentration of adult and fetal tissues of several species. Q J Exp Med 46:188–193Google Scholar
  379. 379.
    Coady MJ, Wallendorff B, Gagnon DG, Lapointe JY (2002) Identification of a novel Na+/myo-inositol cotransporter. J Biol Chem 277:35219–35224PubMedGoogle Scholar
  380. 380.
    Bissonnette P, Coady MJ, Lapointe JY (2004) Expression of the sodium-myo-inositol cotransporter SMIT2 at the apical membrane of Madin-Darby canine kidney cells. J Physiol-Lond 558:759–768PubMedGoogle Scholar
  381. 381.
    Uldry M, Ibberson M, Horisberger JD, Chatton JY, Riederer BM, Thorens B (2001) Identification of a mammalian H+-myo-inositol symporter expressed predominantly in the brain. EMBO J 20:4467–4477PubMedGoogle Scholar
  382. 382.
    Uldry M, Steiner P, Zurich MG, Beguin P, Hirling H, Dolci W, Thorens B (2004) Regulated exocytosis of an H+/myo-inositol symporter at synapses and growth cones. EMBO J 23:531–540PubMedGoogle Scholar
  383. 383.
    Moore CM, Breeze JL, Kukes TL, Rose SL, Dager SR, Cohen BM, Renshaw PF (1999) Effects of myo-inositol ingestion on human brain myo-inositol levels: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatr 45:1197–1202Google Scholar
  384. 384.
    Lubrich B, Spliess O, Gebicke-Haerter P-J, van Calker D (2000) Differential expression, activity and regulation of the sodium/myo-inositol cotransporter in astrocyte cultures from different regions of the rat brain. Neuropharmacol 39:680–690Google Scholar
  385. 385.
    Shonk T, Ross BD (1995) Role of increased cerebral myo-inositol in the dementia of down syndrome. Magn Reson Med 33:858–861PubMedGoogle Scholar
  386. 386.
    Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park HS, Toyoda A, Ishii K, Totoki Y, Choi DK, Soeda E, Ohki M, Takagi T, Sakaki Y, Taudien S, Blechschmidt K, Polley A, Menzel U, Delabar J, Kumpf K, Lehmann R, Patterson D, Reichwald K, Rump A, Schillhabel M (2000) The DNA sequence of human chromosome 21. Nature 405:311–319PubMedGoogle Scholar
  387. 387.
    Garnett MR, Blamire AM, Corkill RG, Cadoux-Hudson TAD, Rajagopalan B, Styles P (2000) Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury. Brain 123:2046–2054PubMedGoogle Scholar
  388. 388.
    McLaurin J, Golomb R, Jurewicz A, Antel JP, Fraser PE (2000) Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit A beta-induced toxicity. J Biol Chem 275:18495–18502PubMedGoogle Scholar
  389. 389.
    Bersudsky Y, Kaplan Z, Shapiro Y, Agam G, Kofman O, Belmaker RH (1994) Behavioural evidence for the existence of two pools of cellular inositol. Eur Neuropsychopharmacol 4:463–467PubMedGoogle Scholar
  390. 390.
    Michaelis T, Helms G, Merboldt K-D, Hänicke W, Bruhn H, Frahm J (1993) Identification of scyllo-inositol in proton NMR spectra of human brain in vivo. NMR Biomed 6:105–109PubMedGoogle Scholar
  391. 391.
    Hipps PP, Holland WH, Sherman WR (1977) Interconversion of myoinositol and scyllo-inositol with simultaneous formation of neo-inositol by an NADP+ dependent epimerase from bovine brain. Biochem Biophys Res Commun 77:340–346PubMedGoogle Scholar
  392. 392.
    Viola A, Nicoli F, Denis B, Confort-Gouny S, Le Fur Y, Ranjeva JP, Viout P, Cozzone PJ (2004) High cerebral scyllo-inositol: a new marker of brain metabolism disturbances induced by chronic alcoholism. Magn Reson Mater Phys, Biol Med 17:47–61Google Scholar
  393. 393.
    Seaquist ER, Gruetter R (1998) Identification of a high concentration of scyllo-inositol in the brain of a healthy human subject using H-1 and C-13 NMR. Magn Reson Med 39:313–316PubMedGoogle Scholar
  394. 394.
    Choi JK, Carreras I, Dedeoglu A, Jenkins BG (2010) Detection of increased scyllo-inositol in brain with magnetic resonance spectroscopy after dietary supplementation in Alzheimer’s disease mouse models. Neuropharmacol 59:353–357Google Scholar
  395. 395.
    Fenili D, Brown M, Rappaport R, McLaurin J (2007) Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology. J Mol Med-Jmm 85:603–611Google Scholar
  396. 396.
    Nozadze M, Mikautadze E, Lepsveridze E, Mikeladze E, Kuchiashvili N, Kiguradze T, Kikvidze M, Solomonia R (2011) Anticonvulsant activities of myo-inositol and scyllo-inositol on pentylenetetrazol induced seizures. Seizure-Eur J Epilepsy 20:173–176Google Scholar
  397. 397.
    Bittar PG, Charnay Y, Pellerin L, Bouras C, Magistretti PJ (1996) Selective distribution of lactate dehydrogenase isoenzymes in neurons and astrocytes of human brain. J Cereb Blood Flow Metab 16:1079–1089PubMedGoogle Scholar
  398. 398.
    Kashiwaya Y, Sato K, Tsuchiya N, Thomas S, Fell DA, Veech RA, Passonneau JV (1994) Control of glucose utilization in working perfused rat heart. J Biol Chem 269:25502–25514PubMedGoogle Scholar
  399. 399.
    Quistorff B, Grunnet N (2011) The isoenzyme pattern of LDH does not play a physiological role; except perhaps during fast transitions in energy metabolism. Aging-US 3:457–460Google Scholar
  400. 400.
    Deuticke B, Rickert I, Beyer E (1978) Stereoselective, SH-dependent transfer of lactate in mammalian erythrocytes. Biochim Biophys Acta 507:137–155PubMedGoogle Scholar
  401. 401.
    Coady MJ, Chang MH, Charron FA, Plata C, Wallendorff B, Sah JF, Markowitz SD, Romero ME, Lapointe JY (2004) The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J Physiol-Lond 557:719–731PubMedGoogle Scholar
  402. 402.
    Gopal E, Umapathy NS, Martin PM, Ananth S, Gnana-Prakasam JP, Becker H, Wagner CA, Ganapathy V, Prasad PD (2007) Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney. Biochimica Et Biophysica Acta-Biomembranes 1768:2690–2697Google Scholar
  403. 403.
    Bröer S, Rahman B, Pellegri G, Pellerin L, Martin JL, Verleysdonk S, Hamprecht B, Magistretti PJ (1997) Comparison of lactate transport in astroglial cells and transporter 1 (MCT 1) expressing Xenopus laevis oocytes. Expression of two different monocarboxylate transporters in astroglial cells and neurons. J Biol Chem 272:30096–30102PubMedGoogle Scholar
  404. 404.
    Martin PM, Gopal E, Ananth S, Zhuang L, Itagaki S, Prasad BM, Smith SB, Prasad PD, Ganapathy V (2006) Identify of SMCT1(SLC5A8) as a neuron-specific Na+ -coupled transporter for active uptake of l-lactate and ketone bodies in the brain. J Neurochem 98:279–288PubMedGoogle Scholar
  405. 405.
    Dringen R, Wiesinger H, Hamprecht B (1993) Uptake of L-lactate by cultured rat brain neurons. Neurosci Lett 163:5–7PubMedGoogle Scholar
  406. 406.
    Walz W, Mukerji S (1988) Lactate release from cultured astrocytes and neurons: a comparison. Glia 1:366–370PubMedGoogle Scholar
  407. 407.
    Herzig S, Raemy E, Montessuit S, Veuthey JL, Zamboni N, Westermann B, Kunji ERS, Martinou JC (2012) Identification and functional expression of the mitochondrial pyruvate carrier. Science 337:93–96PubMedGoogle Scholar
  408. 408.
    Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, Cox JE, Cardon CM, Van Vranken JG, Dephoure N, Redin C, Boudina S, Gygi SP, Brivet M, Thummel CS, Rutter JA (2012) Mitochondrial pyruvate carrier required for pyruvate uptake in yeast, drosophila, and humans. Science 337:96–100PubMedCentralPubMedGoogle Scholar
  409. 409.
    Halestrap AP (1975) The mitochondrial pyruvate carrier. Kinetics and specificity for substrates and inhibitors. Biochem J 148:85–96PubMedGoogle Scholar
  410. 410.
    Halestrap AP, Denton RM (1974) Specific inhibition of pyruvate transport in rat liver mitochondria and human erythrocytes by a-cyano-4-hydroxycinnamate. Biochem J 138:313–316PubMedGoogle Scholar
  411. 411.
    Martin PM, Dun Y, Mysona B, Ananth S, Roon P, Smith SB, Ganapathy V (2007) Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina. Invest Ophthalmol Vis Sci 48:3356–3363PubMedGoogle Scholar
  412. 412.
    Cornford EM, Cornford ME (1986) Nutrient transport and the blood brain barrier in developing animals. Fed Proc 45:2065–2072PubMedGoogle Scholar
  413. 413.
    Medina JM, Tabernero A, Tovar A, Martin-Barrientos J (1996) Metabolic fuel utilisation and pyruvate oxidation during the postnatal period. J Inher Metab Disord 19:432–442Google Scholar
  414. 414.
    Cremer JE, Braun LD, Oldendorf WH (1976) Changes during development in transport processes of the blood-brain barrier. Biochim Biophys Acta 448:633–637PubMedGoogle Scholar
  415. 415.
    Magistretti PJ, Pellerin L (1996) Cellular bases of brain energy metabolism and their relevance to functional brain imaging: evidence for a prominent role of astrocytes. Cereb Cortex 6:50–61PubMedGoogle Scholar
  416. 416.
    Silver IA, Erecinska M (1994) Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo- and hyperglycaemic animals. J Neurosci 14:5068–5076PubMedGoogle Scholar
  417. 417.
    Fox PT, Raichle ME (1986) Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci (USA) 83:1140–1144Google Scholar
  418. 418.
    Fox PT, Raichle ME, Mintun MA, Dence C (1988) Non-oxidative glucose consumption during focal physiological neuronal activity. Science 241:462–464PubMedGoogle Scholar
  419. 419.
    Lowry JP, Fillenz M (1997) Evidence for uncoupling of oxygen and glucose utilization during neuronal activation in rat striatum. J Physiol 498(2):497–501PubMedGoogle Scholar
  420. 420.
    Madsen PL, Cruz NF, Sokoloff L, Dienel GA (1999) Cerebral oxygen/glucose ratio is low during sensory stimulation and rises above normal during recovery: excess glucose consumption during stimulation is not accounted for by lactate efflux from or accumulation in brain tissue. J Cereb Blood Flow Metab 19:393–400PubMedGoogle Scholar
  421. 421.
    Contreras L, Satrustegui J (2009) Calcium signaling in brain mitochondria. Interplay of malate aspartate NADH shuttle and calcium uniporter/mitochondrial dehydrogenase pathways. J Biol Chem 284:7091–7099PubMedGoogle Scholar
  422. 422.
    Dienel GA, Hertz L (2001) Glucose and lactate metabolism during brain activation. J Neurosci Res 66:824–838PubMedGoogle Scholar
  423. 423.
    Cruz NF, Ball KK, Dienel GA (2007) Functional imaging of focal brain activation in conscious rats: impact of [C-14]glucose metabolite spreading and release. J Neurosci Res 85:3254–3266PubMedGoogle Scholar
  424. 424.
    Dienel G, Ball K, Popp D, Cruz NF (2001) A role for gap junctions in metabolite spreading? J Neurochem 78(suppl 1):86Google Scholar
  425. 425.
    Cruz NF, Adachi K, Dienel GA (1999) Rapid efflux of lactate from cerebral cortex during K+-induced spreading cortical depression. J Cereb Blood Flow Metab 19:380–392PubMedGoogle Scholar
  426. 426.
    Ball KK, Cruz NF, Mrak RE, Dienel GA (2010) Trafficking of glucose, lactate, and amyloid-beta from the inferior colliculus through perivascular routes. J Cereb Blood Flow Metab 30:162–176PubMedGoogle Scholar
  427. 427.
    Mangia S, Simpson IA, Vannucci SJ, Carruthers A (2009) The in vivo neuron-to-astrocyte lactate shuttle in human brain: evidence from modeling of measured lactate levels during visual stimulation. J Neurochem 109:55–62PubMedCentralPubMedGoogle Scholar
  428. 428.
    Levasseur JE, Alessandri B, Reinert M, Clausen T, Zhou ZW, Altemeni N, Bullock MR (2006) Lactate not glucose, up-regulates mitochondrial oxygen consumption both in sham and lateral fluid percussed rat brains. Neurosurgery 59:1122–1130PubMedGoogle Scholar
  429. 429.
    Gonzalez SV, Nguyen NHT, Rise F, Hassel B (2005) Brain metabolism of exogenous pyruvate. J Neurochem 95:284–293PubMedGoogle Scholar
  430. 430.
    Schurr A, West CA, Rigor BM (1988) Lactate-supported synaptic function in the rat hippocampal slices preparation. Science 240:1326–1328PubMedGoogle Scholar
  431. 431.
    Schurr A, Payne RS, Miller JJ, Rigor BM (1997) Brain lactate is an obligatory aerobic substrate for functional recovery after hypoxia: further in vitro validation. J Neurochem 69:423–426PubMedGoogle Scholar
  432. 432.
    Cox DWG, Bachelard HS (1988) Partial attenuation of dentate granule cell evoked activity by the alternative substrates, lactate and pyruvate: evidence for a postsynaptic action. Exp Brain Res 69:368–372PubMedGoogle Scholar
  433. 433.
    Yamane K, Yokono K, Okada Y (2000) Anaerobic glycolysis is crucial for the maintenance of neural activity in guinea pig hippocampal slices. J Neurosci Meth 103:163–171Google Scholar
  434. 434.
    McKenna MC, Hopkins IB, Carey A (2001) Alpha-cyano-4-hydroxycinnamate decreases both glucose and lactate metabolism in neurons and astrocytes: implications for lactate as an energy substrate for neurons. J Neurosci Res 66:747–754PubMedGoogle Scholar
  435. 435.
    Petroff OA, Prichard JW, Behar KL, Rothman DL, Alger JR, Shulman RG (1985) Cerebral metabolism in hyper- and hypo-carbia: 31P and 1H nuclear magnetic resonance studies. Neurology 35:1681–1688PubMedGoogle Scholar
  436. 436.
    Rosenberg AA (1988) Response of the cerebral circulation to profound hypocarbia in neonatal lambs. Stroke 19:1365–1370PubMedGoogle Scholar
  437. 437.
    Maddock RJ, Casazza GA, Buonocore MH, Tanase C (2011) Vigorous exercise increases brain lactate and Glx (glutamate plus glutamine): a dynamic 1H-MRS study. Neuroimage 57:1324–1330PubMedGoogle Scholar
  438. 438.
    Dalsgaard MK, Quistorff B, Danielsen ER, Selmer C, Vogelsang T, Secher NH (2004) A reduced cerebral metabolic ratio in exercise reflects metabolism and not accumulation of lactate within the human brain. J Physiol-Lond 554:571–578PubMedGoogle Scholar
  439. 439.
    Dager SR, Marro KI, Richards TL, Metzger GD (1992) Localised magnetic resonance spectroscopy measurement of brain lactate during intravenous lactate infusion in healthy volunteers. Life Science 51:973–985Google Scholar
  440. 440.
    Naylor E, Aillon DV, Barrett BS, Wilson GS, Johnson DA, Johnson DA, Harmon HP, Gabbert S, Petillo PA (2012) Lactate as a biomarker for sleep. Sleep 35:1209–1222PubMedGoogle Scholar
  441. 441.
    Edden RAE, Harris AD, Murphy K, Evans CJ, Saxena N, Hall JE, Bailey DM, Wise RG (2010) Edited MRS is sensitive to changes in lactate concentration during inspiratory hypoxia. J Magn Reson Imag 32:320–325Google Scholar
  442. 442.
    Ben-Joseph O, Bader-Gofer RS, Morris PG, Bachelard HS (1993) Glycerol-3-phosphate and lactate as indicators of cytoplasmic redox state in severe and mild hypoxia respectively; a 13C and 31P NMR study. Biochem J 291:915–919Google Scholar
  443. 443.
    Van Rijen PC, Luyten PR, Berkelbach van der Sprenkel JW, Kraaier V, van Huffelen AC, Tulleken AF, den Hollander JA (1989) 1H and 31P NMR measurements of cerebral lactate, high-energy phosphate levels and pH in humans during voluntary hyperventilation: associated EEG, capnographic and Doppler findings. Magn Reson Med 10:182–193PubMedGoogle Scholar
  444. 444.
    Bell JD, Brown JC, Kubal G, Sadler PJ (1988) NMR-invisible lactate in blood plasma. FEBS Lett 235:81–86PubMedGoogle Scholar
  445. 445.
    Williams SR, Proctor E, Allen K, Gadian DG, Crockard HA (1988) Quantitative estimation of lactate in the brain by 1H NMR. Magn Reson Med 7:425–431PubMedGoogle Scholar
  446. 446.
    Graham GD, Blamire AM, Rothman DL, Brass LM, Fayad PB, Petroff OA, Prichard JW (1993) Early temporal variation of cerebral metabolites after human stroke. A proton magnetic resonance spectroscopy study. Stroke 24:1891–1896PubMedGoogle Scholar
  447. 447.
    Mangia S, Tkac I, Gruetter R, Van de Moortele PF, Maraviglia B, Ugurbil K (2007) Sustained neuronal activation raises oxidative metabolism to a new steady-state level: evidence from H-1 NMR spectroscopy in the human visual cortex. J Cereb Blood Flow Metab 27:1055–1063PubMedGoogle Scholar
  448. 448.
    Sarchielli P, Tarducci R, Presciutti O, Gobbi G, Pelliccioli GP, Stipa G, Alberti A, Capocchi G (2005) Functional H-1-MRS findings in migraine patients with and without aura assessed interictally. Neuroimage 24:1025–1031PubMedGoogle Scholar
  449. 449.
    Richards TL, Dager SR, Corina D, Serafini S, Heide AC, Steury K, Strauss W, Hayes CE, Abbott RD, Craft S, Shaw D, Posse S, Berninger VW (1999) Dyslexic children have abnormal brain lactate response to reading-related language tasks. Am J Neuroradiol 20:1393–1398PubMedGoogle Scholar
  450. 450.
    Richards TL, Corina D, Serafini S, Steury K, Echelard DR, Dager SR, Marro K, Abbott RD, Maravilla KR, Berninger VW (2000) Effects of a phonologically driven treatment for dyslexia on lactate levels measured by proton MR spectroscopy imaging. Am J Neuroradiol 21:916–922PubMedGoogle Scholar
  451. 451.
    Gjedde A, Poulsen PH, Østergaard L (1999) On the oxygenation of hemoglobin in the human brain. Adv Exp Med Biol 471:81–97Google Scholar
  452. 452.
    Maher AD, Solo V, Rae CD (2013) Magnetic resonance-based metabolomics for understanding neurological disorders: current status and considerations. Curr Metabolomics 1:2–14Google Scholar
  453. 453.
    Tisell A, Dahlqvist LO, Warntjes J, Lundberg P (2013) Procedure for quantitative 1H MRS and tissue characterization of human brain tissue based on the use of quantitative MRI. Magn Reson Med 70:905–915Google Scholar
  454. 454.
    Scheidigger O, Wingeier K, Stefan D, Graveron-Demilly D, van Ormondt D, Wiest R, Slotboom J (2013) Optimized quantitative magnetic resonance spectroscopy for clinical routine. Magn Reson Med 70:25–32Google Scholar
  455. 455.
    Steen RG, Ogg RJ (2005) Abnormally high levels of brain N-acetylaspartate in children with sickle cell disease. Am J Neuroradiol 26:463–468PubMedGoogle Scholar
  456. 456.
    Hwang JH, Graham GD, Behar KL, Alger JR, Prichard JW, Rothman DL (1996) Short echo time proton magnetic resonance spectroscopic imaging of macromolecule and metabolite signal intensities in the human brain. Magn Reson Med 35:633–639PubMedGoogle Scholar
  457. 457.
    Mader I, Seeger U, Karitzky J, Erb M, Schick F, Klose U (2002) Proton magnetic resonance spectroscopy with metabolite nulling reveals regional differences of macromolecules in normal human brain. J Magn Reson Imag 16:538–546Google Scholar
  458. 458.
    Seeger U, Klose U, Mader I, Grodd W, Nagele T (2003) Parameterized evaluation of macromolecules and lipids in proton MR spectroscopy of brain diseases. Magn Reson Med 49:19–28PubMedGoogle Scholar
  459. 459.
    Miyake M, Morino H, Mizobuchi M, Kakimoto Y (1982) N-Acetyl-l-aspartic acid, N-acetyl-alpha-l-aspartyl-l-glutamic acid and beta-citryl-l-glutamic acid in human urine. Clin Chim Acta 120:119–126PubMedGoogle Scholar
  460. 460.
    Ruggieri M, Tortorella C, Ceci E, Paolicelli D, Solfrizzi V, Di Bitonto G, Pica C, Mastrapasqua M, Livrea P, Trojano M (2011) Age-related changes of serum N-acetyl-aspartate in healthy controls. Age Ageing 40:391–395PubMedGoogle Scholar
  461. 461.
    Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AMA (2007) N-acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 81:89–131PubMedCentralPubMedGoogle Scholar
  462. 462.
    Béard E, Braissant O (2010) Synthesis and transport of creatine in the CNS: importance for cerebral functions. J Neurochem 115:297–313PubMedGoogle Scholar
  463. 463.
    Kottke M, Wallimann T, Brdiczka D (1994) Dual electron microscopic localization of mitochondrial creatine kinase in brain mitchondria. Biochem Med Metab Biol 51:105–117PubMedGoogle Scholar
  464. 464.
    Nies AT, Jedlitschky G, Konig J, Herold-Mende C, Steiner HH, Schmitt HP, Keppler D (2004) Expression and immunolocalization of the multidrug resistance proteins, Mrp1-Mrp6 (ABCC1–ABCC6), in human brain. Neuroscience 129:349–360PubMedGoogle Scholar
  465. 465.
    Aoyama K, Suh SW, Hamby AM, Liu JL, Chan WY, Chen YM, Swanson RA (2006) Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci 9:119–126PubMedGoogle Scholar
  466. 466.
    Shanker G, Allen JW, Mutkus LA, Aschner M (2001) The uptake of cysteine in cultured primary astrocytes and neurons. Brain Res 902:156–163PubMedGoogle Scholar
  467. 467.
    Rae C, Fekete AD, Kashem MA, Nasrallah FA, Nasrallah FA, Bröer S (2012) Metabolism, compartmentation, transport and production of acetate in the cortical brain tissue slice. Neurochem Res 37:2541–2553PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Neuroscience Research AustraliaRandwickAustralia
  2. 2.Brain SciencesThe University of New South WalesKensingtonAustralia

Personalised recommendations