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Metabolism Changes During Aging in the Hippocampus and Striatum of Glud1 (Glutamate Dehydrogenase 1) Transgenic Mice

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Abstract

The decline in neuronal function during aging may result from increases in extracellular glutamate (Glu), Glu-induced neurotoxicity, and altered mitochondrial metabolism. To study metabolic responses to persistently high levels of Glu at synapses during aging, we used transgenic (Tg) mice that over-express the enzyme Glu dehydrogenase (GDH) in brain neurons and release excess Glu in synapses. Mitochondrial GDH is important in amino acid and carbohydrate metabolism and in anaplerotic reactions. We monitored changes in nineteen neurochemicals in the hippocampus and striatum of adult, middle aged, and aged Tg and wild type (wt) mice, in vivo, using proton (1H) magnetic resonance spectroscopy. Significant differences between adult Tg and wt were higher Glu, N-acetyl aspartate (NAA), and NAA + NAA–Glu (NAAG) levels, and lower lactate in the Tg hippocampus and striatum than those of wt. During aging, consistent changes in Tg and wt hippocampus and striatum included increases in myo-inositol and NAAG. The levels of glutamine (Gln), a key neurochemical in the Gln-Glu cycle between neurons and astroglia, increased during aging in both the striatum and hippocampus of Tg mice, but only in the striatum of the wt mice. Age-related increases of Glu were observed only in the striatum of the Tg mice.

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References

  1. Cotman CW, Monaghan DT, Ganong AH (1988) Excitatory amino acid neurotransmission: NMDA receptors and Hebb-type synaptic plasticity. Annu Rev Neurosci 11:61–80

    Article  CAS  PubMed  Google Scholar 

  2. Michaelis EK (1998) Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol 54:369–415

    Article  CAS  PubMed  Google Scholar 

  3. Ito M (1989) Long-term depression. Annu Rev Neurosci 12:85–102

    Article  CAS  PubMed  Google Scholar 

  4. Bear MF, Abraham WC (1996) Long-term depression in hippocampus. Annu Rev Neurosci 19:437–462

    Article  CAS  PubMed  Google Scholar 

  5. Mattson MP (2008) Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann NY Acad Sci 1144:97–112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Cheng A, Hou Y, Mattson MP (2010) Mitochondria and neuroplasticity. ASN Neuro 2(5):e00045. doi:10.1042/AN20100019

    Article  PubMed Central  PubMed  Google Scholar 

  7. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 88:6368–6371

    Article  CAS  PubMed  Google Scholar 

  8. Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, Tymianski M (2003) A key role for TRPM7 channels in anoxic neuronal death. Cell 115:863–877

    Article  CAS  PubMed  Google Scholar 

  9. Lafon-Cazal M, Culcasi M, Gaven F, Pietri S, Bockaert J (1993) Nitric oxide, superoxide and peroxynitrite: putative mediators of NMDA-induced cell death in cerebellar granule cells. Neuropharmacology 32:1259–1266

    Article  CAS  PubMed  Google Scholar 

  10. Meldrum B, Evans M, Griffiths T, Simon R (1985) Ischaemic brain damage: the role of excitatory activity and of calcium entry. Br J Anaesth 57:44–46

    Article  CAS  PubMed  Google Scholar 

  11. Arundine M, Tymianski M (2003) Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 34:325–337

    Article  CAS  PubMed  Google Scholar 

  12. Choi DW (1992) Excitotoxic cell death. J Neurobiol 23:1261–1276

    Article  CAS  PubMed  Google Scholar 

  13. Dawson VL, Dawson TM (1998) Nitric oxide in neurodegeneration. Prog Brain Res 118:215–229

    Article  CAS  PubMed  Google Scholar 

  14. Zoia C, Cogliati T, Tagliabue E, Cavaletti G, Sala G, Galimberti G, Rivolta I, Rossi V, Frattola L, Ferrarese C (2004) Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer’s disease. Neurobiol Aging 25:149–157

    Article  CAS  PubMed  Google Scholar 

  15. Nickell J, Pomerleau F, Allen J, Gerhardt GA (2005) Age-related changes in the dynamics of potassium-evoked L-glutamate release in the striatum of Fischer 344 rats. J Neural Transm 112:87–96

    Article  CAS  PubMed  Google Scholar 

  16. Zoia CP, Tagliabue E, Isella V, Begni B, Fumagalli L, Brighina L, Appollonio I, Racchi M, Ferrarese C (2005) Fibroblast glutamate transport in aging and in AD: correlations with disease severity. Neurobiol Aging 26:825–832

    Article  CAS  PubMed  Google Scholar 

  17. Brewer GJ (2000) Neuronal plasticity and stressor toxicity during aging. Exp Gerontol 35:1165–1183

    Article  CAS  PubMed  Google Scholar 

  18. Chauhan N, Siegel G (1997) Age-dependent organotypic expression of microtubule-associated proteins (MAP1, MAP2, and MAP5) in rat brain. Neurochem Res 22:713–719

    Article  CAS  PubMed  Google Scholar 

  19. Di Stefano G, Casoli T, Fattoretti P, Gracciotti N, Solazzi M, Bertoni-Freddari C (2001) Distribution of map2 in hippocampus and cerebellum of young and old rats by quantitative immunohistochemistry. J Histochem Cytochem 49:1065–1066

    Article  PubMed  Google Scholar 

  20. Di Stefano G, Casoli T, Fattoretti P, Balietti M, Grossi Y, Giorgetti B, Bertoni-Freddari C (2006) Level and distribution of microtubule-associated protein-2 (MAP2) as an index of dendritic structural dynamics. Rejuvenation Res 9:94–98

    Article  PubMed  Google Scholar 

  21. Arias C, Arrieta I, Massieu L, Tapia R (1997) Neuronal damage and MAP2 changes induced by the glutamate transport inhibitor dihydrokainate and by kainate in rat hippocampus in vivo. Exp Brain Res 116:467–476

    Article  CAS  PubMed  Google Scholar 

  22. Hoskison MM, Yanagawa Y, Obata K, Shuttleworth CW (2007) Calcium-dependent NMDA-induced dendritic injury and MAP2 loss in acute hippocampal slices. Neuroscience 145:66–79.

    Google Scholar 

  23. Buddle M, Eberhardt E, Ciminello LH, Levin T, Wing R, DiPasquale K, Raley-Susman KM (2003) Microtubule-associated protein 2 (MAP2) associates with the NMDA receptor and is spatially redistributed within rat hippocampal neurons after oxygen-glucose deprivation. Brain Res 978:38–50

    Article  CAS  PubMed  Google Scholar 

  24. Sánchez C, Ulloa L, Montoro RJ, López-Barneo J, Avila J (1997) NMDA-glutamate receptors regulate phosphorylation of dendritic cytoskeletal proteins in the hippocampus. Brain Res 765:141–148

    Article  PubMed  Google Scholar 

  25. Quinlan EM, Halpain S (1996) Postsynaptic mechanisms for bidirectional control of MAP2 phosphorylation by glutamate receptors. Neuron 16:357–368

    Article  CAS  PubMed  Google Scholar 

  26. Arundine M, Tymianski M (2004) Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci 61:657–668

    Article  CAS  PubMed  Google Scholar 

  27. Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11:682–696

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Kabuto H, Yokoi I, Mori A, Murakami M, Sawada S (1995) Neurochemical changes related to ageing in the senescence-accelerated mouse brain and the effect of chronic administration of nimodipine. Mech Ageing Dev 80:1–9

    Article  CAS  PubMed  Google Scholar 

  29. Gozlan H, Daval G, Verge D, Spampinato U, Fattaccini CM, Gallissot MC, El Mestikawy S, Hamon M (1990) Aging associated changes in serotoninergic and dopaminergic pre- and post-synaptic neurochemical markers in the rat brain. Neurobiol Aging 11:437–449

    Article  CAS  PubMed  Google Scholar 

  30. Gottfries CG (1990) Neurochemical aspects on aging and diseases with cognitive impairment. J Neurosci Res 27:541–547

    Article  CAS  PubMed  Google Scholar 

  31. Murphy DG, DeCarli C, McIntosh AR, Daly E, Mentis MJ, Pietrini P, Szczepanik J, Schapiro MB, Grady CL, Horwitz B, Rapoport SI (1996) Sex differences in human brain morphometry and metabolism: an in vivo quantitative magnetic resonance imaging and positron emission tomography study on the effect of aging. Arch Gen Psychiatry 53:585–594

    Article  CAS  PubMed  Google Scholar 

  32. Gage F, Kelly P, Bjorklund A (1984) Regional changes in brain glucose metabolism reflect cognitive impairments in aged rats. J Neurosci 4:2856–2865

    CAS  PubMed  Google Scholar 

  33. Boumezbeur F, Mason GF, de Graaf RA, Behar KL, Cline GW, Shulman GI, Rothman DL, Petersen KF (2010) Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy. J Cereb Blood Flow Metab 30:211–221

    Article  CAS  PubMed  Google Scholar 

  34. Matsugami TR, Tanemura K, Mieda M, Nakatomi R, Yamada K, Kondo T, Ogawa M, Obata K, Watanabe M, Hashikawa T, Tanaka K (2006) From the cover: indispensability of the glutamate transporters GLAST and GLT1 to brain development. Proc Natl Acad Sci USA 103:12161–12166

    Article  CAS  PubMed  Google Scholar 

  35. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF (1996) Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16:675–686

    Article  CAS  PubMed  Google Scholar 

  36. Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699–1702

    Article  CAS  PubMed  Google Scholar 

  37. Zeng LH, Ouyang Y, Gazit V, Cirrito JR, Jansen LA, Ess KC, Yamada KA, Wozniak DF, Holtzman DM, Gutmann DH, Wong M (2007) Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex. Neurobiol Dis 28:184–196

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Bao X, Pal R, Hascup KN, Wang Y, Wang WT, Xu W, Hui D, Agbas A, Wang X, Michaelis ML, Choi IY, Belousov AB, Gerhardt GA, Michaelis EK (2009) Transgenic expression of Glud1 (glutamate dehydrogenase 1) in neurons: in vivo model of enhanced glutamate release, altered synaptic plasticity, and selective neuronal vulnerability. J Neurosci 29:13929–13944

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Michaelis EK, Wang X, Pal R, Bao X, Hascup KN, Wang Y, Wang WT, Hui D, Agbas A, Choi IY, Belousov A, Gerhardt GA (2011) Neuronal Glud1 (glutamate dehydrogenase 1) over-expressing mice: increased glutamate formation and synaptic release, loss of synaptic activity, and adaptive changes in genomic expression. Neurochem Int 59:473–481

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Hascup KN, Bao X, Hascup ER, Hui D, Xu W, Pomerleau F, Huettl P, Michaelis ML, Michaelis EK, Gerhardt GA (2011) Differential levels of glutamate dehydrogenase 1 (GLUD1) in Balb/c and C57BL/6 mice and the effects of overexpression of the Glud1 gene on glutamate release in striatum. ASN Neuro 3(2):e00057. doi:10.1042/AN20110005

    Google Scholar 

  41. Plaitakis A, Zaganas I, Spanaki C (2013) Deregulation of glutamate dehydrogenase in human neurologic disorders. J Neurosci Res 91:1007–1017

    Article  CAS  PubMed  Google Scholar 

  42. Choi IY, Lee SP, Guilfoyle DN, Helpern JA (2003) In vivo NMR studies of neurodegenerative diseases in transgenic and rodent models. Neurochem Res 28:987–1001

    Article  CAS  PubMed  Google Scholar 

  43. Pfeuffer J, Tkac I, Provencher SW, Gruetter R (1999) Toward an in vivo neurochemical profile: quantification of 18 metabolites in short-echo-time (1)H NMR spectra of the rat brain. J Magn Reson 141:104–120

    Article  CAS  PubMed  Google Scholar 

  44. Mlynarik V, Gambarota G, Frenkel H, Gruetter R (2006) Localized short-echo-time proton MR spectroscopy with full signal-intensity acquisition. Magn Reson Med 56:965–970

    Article  CAS  PubMed  Google Scholar 

  45. Gruetter R (1993) Automatic, localized in vivo adjustment of all first- and second-order shim coils. Magn Reson Med 29:804–811

    Article  CAS  PubMed  Google Scholar 

  46. Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679

    Article  CAS  PubMed  Google Scholar 

  47. Strimmer K (2008) fdrtool: a versatile R package for estimating local and tail area-based false discovery rates. Bioinformatics 24:1461–1462

    Article  CAS  PubMed  Google Scholar 

  48. Team RC (2012) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna. http://www.R-project.org/

  49. Belanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte–neuron metabolic cooperation. Cell Metab 14:724–738

    Article  CAS  PubMed  Google Scholar 

  50. Magistretti PJ, Pellerin L (1999) Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging. Philos Trans R Soc Lond Ser B Biol Sci 354:1155–1163

    Article  CAS  Google Scholar 

  51. Wang X, Michaelis EK (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2:12

    PubMed Central  PubMed  Google Scholar 

  52. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP (2009) The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C–Cdh1. Nat Cell Biol 11:747–752

    Article  CAS  PubMed  Google Scholar 

  53. Boumezbeur F, Petersen KF, Cline GW, Mason GF, Behar KL, Shulman GI, Rothman DL (2010) The contribution of blood lactate to brain energy metabolism in humans measured by dynamic 13C nuclear magnetic resonance spectroscopy. J Neurosci 30:13983–13991

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Wang X, Pal R, Chen XW, Kumar KN, Kim OJ, Michaelis EK (2007) Genome-wide transcriptome profiling of region-specific vulnerability to oxidative stress in the hippocampus. Genomics 90:201–212

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Wang X, Pal R, Chen XW, Limpeanchob N, Kumar KN, Michaelis EK (2005) High intrinsic oxidative stress may underlie selective vulnerability of the hippocampal CA1 region. Brain Res Mol Brain Res 140:120–126

    Article  CAS  PubMed  Google Scholar 

  56. Wang X, Zaidi A, Pal R, Garrett AS, Braceras R, Chen XW, Michaelis ML, Michaelis EK (2009) Genomic and biochemical approaches in the discovery of mechanisms for selective neuronal vulnerability to oxidative stress. BMC Neurosci 10:12

    Article  PubMed Central  PubMed  Google Scholar 

  57. Wang X, Michaelis ML, Michaelis EK (2010) Functional genomics of brain aging and Alzheimer’s disease: focus on selective neuronal vulnerability. Curr Genomics 11:618–633

    Article  PubMed  Google Scholar 

  58. Banay-Schwartz M, Lajtha A, Palkovits M (1989) Changes with aging in the levels of amino acids in rat CNS structural elements I. Glutamate and related amino acids. Neurochem Res 14:555–562

    Article  CAS  PubMed  Google Scholar 

  59. Kaiser LG, Schuff N, Cashdollar N, Weiner MW (2005) Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T. Neurobiol Aging 26:665–672

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Crumrine RC, LaManna JC (1991) Regional cerebral metabolites, blood flow, plasma volume, and mean transit time in total cerebral ischemia in the rat. J Cereb Blood Flow Metab 11:272–282

    Article  CAS  PubMed  Google Scholar 

  61. Neale JH, Bzdega T, Wroblewska B (2000) N-acetylaspartylglutamate: the most abundant peptide neurotransmitter in the mammalian central nervous system. J Neurochem 75:443–452

    Article  CAS  PubMed  Google Scholar 

  62. Friedman SD, Brooks WM, Jung RE, Chiulli SJ, Sloan JH, Montoya BT, Hart BL, Yeo RA (1999) Quantitative proton MRS predicts outcome after traumatic brain injury. Neurology 52:1384–1391

    Article  CAS  PubMed  Google Scholar 

  63. Brooks WM, Jung RE, Ford CC, Greinel EJ, Sibbitt WL Jr (1999) Relationship between neurometabolite derangement and neurocognitive dysfunction in systemic lupus erythematosus. J Rheumatol 26:81–85

    CAS  PubMed  Google Scholar 

  64. Harris JL, Yeh HW, Choi IY, Lee P, Berman NE, Swerdlow RH, Craciunas SC, Brooks WM (2012) Altered neurochemical profile after traumatic brain injury: (1)H-MRS biomarkers of pathological mechanisms. J Cereb Blood Flow Metab 32:2122–2134

    Article  CAS  PubMed  Google Scholar 

  65. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM (2007) N-acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 81:89–131

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. 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 184:539–546

    CAS  PubMed  Google Scholar 

  67. Satrustegui J, Contreras L, Ramos M, Marmol P, del Arco A, Saheki T, Pardo B (2007) Role of aralar, the mitochondrial transporter of aspartate–glutamate, in brain N-acetylaspartate formation and Ca(2+) signaling in neuronal mitochondria. J Neurosci Res 85:3359–3366

    Article  CAS  PubMed  Google Scholar 

  68. Clark JF, Doepke A, Filosa JA, Wardle RL, Lu A, Meeker TJ, Pyne-Geithman GJ (2006) N-acetylaspartate as a reservoir for glutamate. Med Hypotheses 67:506–512

    Article  CAS  PubMed  Google Scholar 

  69. Saransaari P, Oja SS (1995) Age-related changes in the uptake and release of glutamate and aspartate in the mouse brain. Mech Ageing Dev 81:61–71

    Article  CAS  PubMed  Google Scholar 

  70. Neale JH, Olszewski RT, Zuo D, Janczura KJ, Profaci CP, Lavin KM, Madore JC, Bzdega T (2011) Advances in understanding the peptide neurotransmitter NAAG and appearance of a new member of the NAAG neuropeptide family. J Neurochem 118:490–498

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Moeller JR, Ishikawa T, Dhawan V, Spetsieris P, Mandel F, Alexander GE, Grady C, Pietrini P, Eidelberg D (1996) The metabolic topography of normal aging. J Cereb Blood Flow Metab 16:385–398

    Article  CAS  PubMed  Google Scholar 

  72. Ançevic VI, Alavi A, Souder E, Mozley PD, Gur RE, Bénard F, Munz DL (2000) Regional cerebral glucose metabolism in healthy volunteers determined by fluordeoxyglucose positron emission tomography: appearance and variance in the transaxial, coronal, and sagittal planes. Clin Nucl Med 25:596–602

    Article  Google Scholar 

  73. Okuma Y, Nomura Y (1998) Senescence-accelerated mouse (SAM) as an animal model of senile dementia: pharmacological, neurochemical and molecular biological approach. Jpn J Pharmacol 78:399–404

    Article  CAS  PubMed  Google Scholar 

  74. Kitamura Y, Zhao XH, Ohnuki T, Takei M, Nomura Y (1992) Age-related changes in transmitter glutamate and NMDA receptor/channels in the brain of senescence-accelerated mouse. Neurosci Lett 137:169–172

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded by grants from the National Institutes of Health, NIA: AG12993 and AG035982; and NICHD: HD02528. The support of the Higuchi Biosciences Center and of the Hoglund Brain Imaging Center at the University of Kansas is acknowledged.

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Authors and Affiliations

  1. Hoglund Brain Imaging Center, University of Kansas Medical Center, Kansas City, KS, USA

    In-Young Choi, Phil Lee, Wen-Tung Wang & William M. Brooks

  2. Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA

    In-Young Choi & William M. Brooks

  3. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA

    In-Young Choi & Phil Lee

  4. Higuchi Biosciences Center, University of Kansas, 2099 Constant Ave., Campus West, Lawrence, KS, 66047, USA

    Dongwei Hui, Xinkun Wang & Elias K. Michaelis

  5. Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA

    Dongwei Hui, Xinkun Wang & Elias K. Michaelis

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  1. In-Young Choi
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Choi, IY., Lee, P., Wang, WT. et al. Metabolism Changes During Aging in the Hippocampus and Striatum of Glud1 (Glutamate Dehydrogenase 1) Transgenic Mice. Neurochem Res 39, 446–455 (2014). https://doi.org/10.1007/s11064-014-1239-9

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