Journal of Neural Transmission

, Volume 116, Issue 3, pp 291–300

Elevated endogenous GABA concentration attenuates glutamate–glutamine cycling between neurons and astroglia

Basic Neurosciences, Genetics and Immunology - Original Article

Abstract

In this study, the relationship between endogenous brain GABA concentration and glutamate–glutamine cycling flux (Vcyc) was investigated using in vivo 1H and 1H{13C} magnetic resonance spectroscopy techniques. Graded elevations of brain GABA levels were induced in rat brain after administration of the highly specific GABA-transaminase inhibitor vigabatrin (γ-vinyl-GABA). The glial-specific substrate [2-13C]acetate and 1H{13C} magnetic resonance spectroscopy were used to measure Vcyc at different GABA levels. Significantly reduced Vcyc was found in rats pretreated with vigabatrin. The reduction in group mean Vcyc over the range of GABA concentrations investigated in this study (1.0 ± 0.3–5.1 ± 0.5 μmol/g) was found to be nonlinear: ΔVcyc/Vcyc = [GABA (μmol/g)]−0.35 − 1.0 (r2 = 0.98). The results demonstrate that Vcyc is modulated by endogenous GABA levels, and that glutamatergic and GABAergic interactions can be studied in vivo using noninvasive magnetic resonance spectroscopy techniques.

Keywords

GABA Vigabatrin Glutamate Magnetic resonance spectroscopy 

References

  1. Banay-Schwartz M, Palkovits M, Lajtha A (1993) Heterogeneous distribution of functionally important amino acids in brain areas of adult and aging humans. Neurochem Res 18:417–423PubMedCrossRefGoogle Scholar
  2. Bergin AM, Connolly M (2002) New antiepileptic drug therapies. Neurol Clin 20:82–1163Google Scholar
  3. Blüml S, Moreno-Torres A, Shic F, Nguy CH, Ross BD (2002) Tricarboxylic acid cycle of glia in the in vivo human brain. NMR Biomed 15:1–5PubMedCrossRefGoogle Scholar
  4. Boumezbeur F, Petersen KF, de Graaf RA, Cline GW, Behar KL, Shulman GI, Rothman DL, Mason GF (2008) Combination of datasets from [2-13C]acetate and [1-13C]glucose experiments improve accuracy of metabolite rates determination in humans. Proc Intl Soc Magn Reson Med, Abstract # 196, TorontoGoogle Scholar
  5. Bradford HF (1995) Glutamate, GABA and epilepsy. Prog Neurobiol 47:477–511PubMedCrossRefGoogle Scholar
  6. Chapman AG, Riley K, Evens MC, Meldrum BS (1982) Acute effects of sodium valproate and γ-vinyl GABA on regional amino acid metabolism in the rat brain: incorporation of 2-[14C]glucose into amino acids. Neurochem Res 7:1089–1105PubMedCrossRefGoogle Scholar
  7. Chen Z, Li SS, Yang J, Letizia D, Shen J (2004) Measurement and automatic correction of high order B0 inhomogeneity in the rat brain at 11.7 Tesla. Magn Reson Imaging 22:835–842PubMedCrossRefGoogle Scholar
  8. Crowder JM, Bradford HF (1987) Inhibitory effects of noradrenaline and dopamine on calcium influx and neurotransmitter glutamate release in mammalian brain slices. Eur J Pharmacol 143:52–343CrossRefGoogle Scholar
  9. Danbolt NC, Storm-Mathisen J, Kanner BI (1992) An [Na+–K+]coupled l-glutamate transporter purified from rat brain is located in glial cell processes. Neuroscience 51:295–310PubMedCrossRefGoogle Scholar
  10. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC (2007) Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 64:193–200PubMedCrossRefGoogle Scholar
  11. Hertz L (2004) Intercellular metabolic compartmentation in the brain: past, present and future. Neurochem Int 45:285–296PubMedCrossRefGoogle Scholar
  12. 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. Neuropharmacology 39:65–74PubMedCrossRefGoogle Scholar
  13. Kendell SF, Krystal JH, Sanacora G (2005) GABA and glutamate systems as therapeutic targets in depression and mood disorders. Expert Opin Ther Targets 9:153–168PubMedCrossRefGoogle Scholar
  14. Kuzniecky R, Ho S, Pan J, Martin R, Gilliam F, Faught E, Hetherington H (2002) Modulation of cerebral GABA by topiramate, lamotrigine, and gabapentin in healthy adults. Neurology 58:368–372PubMedGoogle Scholar
  15. Lebon V, Petersen KF, Cline GW, Shen J, Mason GF, Dufour S, Behar KL, Shulman GI, Rothman DL (2002) Astroglial contribution to brain energy metabolism in humans revealed by 13C nuclear magnetic resonance spectroscopy: elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism. J Neurosci 22:1523–1531PubMedGoogle Scholar
  16. Manor D, Rothman DL, Mason GF, Hyder F, Petroff OA, Behar KL (1996) The rate of turnover of cortical GABA from [1–13C]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA). Neurochem Res 21:1031–1041PubMedCrossRefGoogle Scholar
  17. Maura G, Marcoli M, Tortarolo M, Andrioli GC, Raiteri M (1998) Glutamate release in human cerebral cortex and its modulation by 5-hydroxytryptamine acting at h 5-HT1D receptors. Br J Pharmacol 123:45–50PubMedCrossRefGoogle Scholar
  18. McDonald DG, Najam Y, Keegan MB, Whooley M, Madden D, McMenamin JB (2005) The use of lamotrigine, vigabatrin and gabapentin as add-on therapy in intractable epilepsy of childhood. Seizure 14:112–116PubMedCrossRefGoogle Scholar
  19. Michaelis T, Merboldt KD, Bruhn H, Hanicke W, Frahm J (1993) Absolute concentrations of metabolites in the adult human brain in vivo: quantification of localized proton MR spectra. Radiology 187:219–227PubMedGoogle Scholar
  20. Michael-Titus AT, Bains S, Jeetle J, Whelpton R (2000) Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex-a possible mechanism of neuroprotection in major depression? Neuroscience 100:681–684PubMedCrossRefGoogle Scholar
  21. Miller JM, Jope RS, Ferraro TN, Hare TA (1990) Brain amino acid concentrations in rats killed by decapitation and microwave irradiation. J Neurosci Methods 31:187–192PubMedCrossRefGoogle Scholar
  22. Parent MB, Habib MK, Baker GB (2000) Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine. Biochem Pharmacol 59:63–1253CrossRefGoogle Scholar
  23. Parent MB, Master S, Kashlub S, Baker GB (2002) Effects of the antidepressant/antipanic drug phenelzine and its putative metabolite phenylethylidenehydrazine on extracellular gamma-aminobutyric acid levels in the striatum. Biochem Pharmacol 63:57–64PubMedCrossRefGoogle Scholar
  24. Patel AB, de Graaf RA, Martin DL, Battaglioli G, Behar KL (2006) Evidence that GAD65 mediates increased GABA synthesis during intense neuronal activity in vivo. J Neurochem 97:385–396PubMedCrossRefGoogle Scholar
  25. Petroff OA, Hyder F, Collins T, Mattson RH, Rothman DL (1999) Acute effects of vigabatrin on brain GABA and homocarnosine in patients with complex partial seizures. Epilepsia 40:64–958CrossRefGoogle Scholar
  26. Piérard C, Pérès M, Satabin P, Guezennec CY, Lagarde D (1999) Effects of GABA-transaminase inhibition on brain metabolism and amino-acid compartmentation: an in vivo study by 2D 1H-NMR spectroscopy coupled with microdialysis. Exp Brain Res 127:321–327PubMedCrossRefGoogle Scholar
  27. Post RM, Denicoff KD, Frye MA, Dunn RT, Leverich GS, Osuch E, Speer A (1998) A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century. Neuropsychobiology 38:66–152CrossRefGoogle Scholar
  28. Preece NE, Cerdan S (1996) Metabolic precursors and compartmentation of cerebral GABA in vigabatrin-treated rats. J Neurochem 67:1718–1725PubMedCrossRefGoogle Scholar
  29. Provencher SW (2001) Automatic quantification of localized in vivo 1H spectra with LCModel. NMR Biomed 14:260–264PubMedCrossRefGoogle Scholar
  30. Qume M, Whitton PS, Fowler LJ (1995) The effect of chronic treatment with the GABA transaminase inhibitors gamma-vinyl-GABA and ethanolamine-O-sulphate on the in vivo release of GABA from rat hippocampus. J Neurochem 64:2256–2261PubMedGoogle Scholar
  31. Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA, Berman RM, Charney DS, Krystal JH (1999) Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 56:1043–1047PubMedCrossRefGoogle Scholar
  32. Schumann WC, Magnusson I, Chandramouli V, Kumaran K, Wahren J, Landau BR (1991) Metabolism of [2–14C]acetate and its use in assessing hepatic Krebs cycle activity and gluconeogenesis. J Biol Chem 266:90–6985Google Scholar
  33. Shen J (2006) 13C magnetic resonance spectroscopy studies of alterations in glutamate neurotransmission. Biol Psychiatry 59:883–887PubMedCrossRefGoogle Scholar
  34. Shen J, Petersen KF, Behar KL, Brown P, Nixon TW, Mason GF, Petroff OA, Shulman GI, Shulman RG, Rothman DL (1999) Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR. Proc Natl Acad Sci USA 96:8235–8240PubMedCrossRefGoogle Scholar
  35. Shen J, Yang J, Choi I-Y, Li SS, Chen Z (2004) A new strategy for in vivo spectral editing Application to GABA editing using selective homonuclear polarization transfer spectroscopy. J Magn Reson 170:290–298PubMedCrossRefGoogle Scholar
  36. Sibson NR, Dhankhar A, Mason GF, Behar KL, Rothman DL, Shulman RG (1997) In vivo 13C NMR measurements of cerebral glutamine synthesis as evidence for glutamate-glutamine cycling. Proc Natl Acad Sci USA 94:2699–2704PubMedCrossRefGoogle Scholar
  37. Slotboom J, Bovée WMMJ (1995) Adiabatic slice-selective rf pulses and a single-shot adiabatic localization pulse sequence. Concept Magn Reson 7:193–217CrossRefGoogle Scholar
  38. Smolders I, Khan GM, Lindekens H, Prikken S, Marvin CA, Manil J, Ebinger G, Michotte Y (1997) Effectiveness of vigabatrin against focally evoked pilocarpine-induced seizures and concomitant changes in extracellular hippocampal and cerebellar glutamate, gamma-aminobutyric acid and dopamine levels, a microdialysis-electrocorticography study in freely moving rats. J Pharmacol Exp Ther 283:1239–1248PubMedGoogle Scholar
  39. Waniewski RA, Martin DL (1998) Preferential utilization of acetate by astrocytes is attributable to transport. J Neurosci 18:5225–5233PubMedGoogle Scholar
  40. Wood JD, Kurylo E, Lane R (1988) Gamma-Aminobutyric acid release from synaptosomes prepared from rats treated with isonicotinic acid hydrazide and gabaculine. J Neurochem 50:1839–1843PubMedCrossRefGoogle Scholar
  41. Wu Y, Wang W, Richerson GB (2003) Vigabatrin induces tonic inhibition via GABA transporter reversal without increasing vesicular GABA release. J Neurophysiol 89:2021–2034PubMedCrossRefGoogle Scholar
  42. Yang J, Shen J (2005) In vivo evidence for reduced cortical glutamate–glutamine cycling in rats treated with the antidepressant/antipanic drug phenelzine. Neuroscience 135:37–927CrossRefGoogle Scholar
  43. Yang J, Li SS, Bacher J, Shen J (2007) Quantification of cortical GABA-glutamine cycling rate using in vivo magnetic resonance signal of [2-13C]GABA derived from glia-specific substrate [2-13C]acetate. Neurochem Int 50:371–378PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Molecular Imaging Branch National Institute of Mental Health Intramural Research Program, National Institutes of HealthBethesdaUSA
  2. 2.Samsung Biomedical Research InstituteSeoulKorea

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