Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia

Subjects

Abstract

Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. American Psychiatric Association. American Psychiatric Association task force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. 4th edn American Psychiatric Association: Washington, DC, 2000). 943. pp xxxvii.

  2. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000; 97: 8104–8109.

    CAS  Article  Google Scholar 

  3. Lewis DA, Moghaddam B . Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. Arch Neurol 2006; 63: 1372–1376.

    Article  Google Scholar 

  4. Tamminga CA, Stan AD, Wagner AD . The hippocampal formation in schizophrenia. Am J Psychiatry 2010; 167: 1178–1193.

    Article  Google Scholar 

  5. Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW et al. NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 1996; 16: 2034–2043.

    CAS  Article  Google Scholar 

  6. Gao XM, Sakai K, Roberts RC, Conley RR, Dean B, Tamminga CA . Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am J Psychiatry 2000; 157: 1141–1149.

    CAS  Article  Google Scholar 

  7. Ghose S, Chin R, Gallegos A, Roberts R, Coyle J, Tamminga C . Localization of NAAG-related gene expression deficits to the anterior hippocampus in schizophrenia. Schizophr Res 2009; 111: 131–137.

    Article  Google Scholar 

  8. Law AJ, Deakin JF . Asymmetrical reductions of hippocampal NMDAR1 glutamate receptor mRNA in the psychoses. Neuroreport 2001; 12: 2971–2974.

    CAS  Article  Google Scholar 

  9. Csernansky JG, Wang L, Jones D, Rastogi-Cruz D, Posener JA, Heydebrand G et al. Hippocampal deformities in schizophrenia characterized by high dimensional brain mapping. Am J Psychiatry 2002; 159: 2000–2006.

    Article  Google Scholar 

  10. Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA . Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br J Psychiatry 2006; 188: 510–518.

    Article  Google Scholar 

  11. Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RS . Patterns of cerebral blood flow in schizophrenia. Br J Psychiatry 1992; 160: 179–186.

    CAS  Article  Google Scholar 

  12. Bogerts B, Ashtari M, Degreef G, Alvir JM, Bilder RM, Lieberman JA . Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Res 1990; 35: 1–13.

    CAS  Article  Google Scholar 

  13. Heckers S, Stone D, Walsh J, Shick J, Koul P, Benes FM . Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch Gen Psychiatry 2002; 59: 521–529.

    CAS  Article  Google Scholar 

  14. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199–214.

    CAS  Article  Google Scholar 

  15. Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA . Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 2001; 25: 455–467.

    CAS  Article  Google Scholar 

  16. Mohn AR, Gainetdinov RR, Caron MG, Koller BH . Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 1999; 98: 427–436.

    CAS  Article  Google Scholar 

  17. Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry 2012; 17: 142–153.

    CAS  Article  Google Scholar 

  18. Marsman A, van den Heuvel MP, Klomp DW, Kahn RS, Luijten PR, Hulshoff Pol HE . Glutamate in schizophrenia: a focused review and meta-analysis of (1)H-MRS studies. Schizophrenia bulletin 2013; 39: 120–129.

    Article  Google Scholar 

  19. Lutkenhoff ES, van Erp TG, Thomas MA, Therman S, Manninen M, Huttunen MO et al. Proton MRS in twin pairs discordant for schizophrenia. Mol Psychiatry 2010; 15: 308–318.

    CAS  Article  Google Scholar 

  20. Hutcheson NL, Reid MA, White DM, Kraguljac NV, Avsar KB, Bolding MS et al. Multimodal analysis of the hippocampus in schizophrenia using proton magnetic resonance spectroscopy and functional magnetic resonance imaging. Schizophr Res 2012; 140: 136–142.

    Article  Google Scholar 

  21. Olbrich HM, Valerius G, Rusch N, Buchert M, Thiel T, Hennig J et al. Frontolimbic glutamate alterations in first episode schizophrenia: evidence from a magnetic resonance spectroscopy study. World J Biol Psychiatry 2008; 9: 59–63.

    Article  Google Scholar 

  22. Kraguljac NV, Reid MA, White DM, den Hollander J, Lahti AC . Regional decoupling of N-acetyl-aspartate and glutamate in schizophrenia. Neuropsychopharmacology 2012; 37: 2635–2642.

    CAS  Article  Google Scholar 

  23. van Elst LT, Valerius G, Buchert M, Thiel T, Rusch N, Bubl E et al. Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study. Biol Psychiatry 2005; 58: 724–730.

    Article  Google Scholar 

  24. da Silva Alves F, Boot E, Schmitz N, Nederveen A, Vorstman J, Lavini C et al. Proton magnetic resonance spectroscopy in 22q11 deletion syndrome. PloS One 2011; 6: e21685.

    Article  Google Scholar 

  25. Kraguljac NV, White DM, Reid MA, Lahti AC . Increased hippocampal glutamate and volumetric deficits in unmedicated patients with schizophrenia. JAMA Psychiatry 2013; 70: 1294–1302.

    CAS  Article  Google Scholar 

  26. Bartha R, al-Semaan YM, Williamson PC, Drost DJ, Malla AK, Carr TJ et al. A short echo proton magnetic resonance spectroscopy study of the left mesial-temporal lobe in first-onset schizophrenic patients. Biol Psychiatry 1999; 45: 1403–1411.

    CAS  Article  Google Scholar 

  27. Galinska B, Szulc A, Tarasow E, Kubas B, Dzienis W, Czernikiewicz A et al. Duration of untreated psychosis and proton magnetic resonance spectroscopy (1H-MRS) findings in first-episode schizophrenia. Med Sci Monit 2009; 15: CR82–CR88.

    Google Scholar 

  28. Fusar-Poli P, Stone JM, Broome MR, Valli I, Mechelli A, McLean MA et al. Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis. Arch Gen Psychiatry 2011; 68: 881–890.

    CAS  Article  Google Scholar 

  29. Valli I, Stone J, Mechelli A, Bhattacharyya S, Raffin M, Allen P et al. Altered medial temporal activation related to local glutamate levels in subjects with prodromal signs of psychosis. Biol Psychiatry 2011; 69: 97–99.

    CAS  Article  Google Scholar 

  30. Wood SJ, Kennedy D, Phillips LJ, Seal ML, Yucel M, Nelson B et al. Hippocampal pathology in individuals at ultra-high risk for psychosis: a multi-modal magnetic resonance study. NeuroImage 2010; 52: 62–68.

    CAS  Article  Google Scholar 

  31. Stone JM, Day F, Tsagaraki H, Valli I, McLean MA, Lythgoe DJ et al. Glutamate dysfunction in people with prodromal symptoms of psychosis: relationship to gray matter volume. Biol Psychiatry 2009; 66: 533–539.

    CAS  Article  Google Scholar 

  32. Lewis DA, Hashimoto T, Volk DW . Cortical inhibitory neurons and schizophrenia. Nature reviews Neuroscience 2005; 6: 312–324.

    CAS  Article  Google Scholar 

  33. Gonzalez-Burgos G, Hashimoto T, Lewis DA . Alterations of cortical GABA neurons and network oscillations in schizophrenia. Curr Psychiatry Rep 2010; 12: 335–344.

    Article  Google Scholar 

  34. Thompson M, Weickert CS, Wyatt E, Webster MJ . Decreased glutamic acid decarboxylase(67) mRNA expression in multiple brain areas of patients with schizophrenia and mood disorders. J Psychiatr Res 2009; 43: 970–977.

    Article  Google Scholar 

  35. Thompson Ray M, Weickert CS, Wyatt E, Webster MJ . Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. J Psychiatry Neurosci 2011; 36: 195–203.

    Article  Google Scholar 

  36. Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H et al. Hippocampal interneurons are abnormal in schizophrenia. Schizophr Res 2011; 131: 165–173.

    Article  Google Scholar 

  37. Kegeles LS, Mao X, Stanford AD, Girgis R, Ojeil N, Xu X et al. Elevated prefrontal cortex gamma-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2012; 69: 449–459.

    CAS  Article  Google Scholar 

  38. Rowland LM, Kontson K, West J, Edden RA, Zhu H, Wijtenburg SA et al. In Vivo Measurements of Glutamate, GABA, and NAAG in Schizophrenia. Schizophr Bull 2013; 39: 1096–1104.

    Article  Google Scholar 

  39. Mescher M, Merkle H, Kirsch J, Garwood M, Gruetter R . Simultaneous in vivo spectral editing and water suppression. NMR Biomed 1998; 11: 266–272.

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  41. Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 2012; 18: 624–629.

    CAS  Article  Google Scholar 

  42. Stan AD, Ghose S, Gao XM, Roberts RC, Lewis-Amezcua K, Hatanpaa KJ et al. Human postmortem tissue: what quality markers matter? Brain Res 2006; 1123: 1–11.

    CAS  Article  Google Scholar 

  43. McHugh TJ, Jones MW, Quinn JJ, Balthasar N, Coppari R, Elmquist JK et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 2007; 317: 94–99.

    CAS  Article  Google Scholar 

  44. Hintze J . NCSS 8. NCSS: Kaysville, UT, USA. 2012.

  45. Eyjolfsson EM, Nilsen LH, Kondziella D, Brenner E, Haberg A, Sonnewald U . Altered 13C glucose metabolism in the cortico-striato-thalamo-cortical loop in the MK-801 rat model of schizophrenia. J Cereb Blood Flow Metab 2011; 31: 976–985.

    CAS  Article  Google Scholar 

  46. Rothman DL, Behar KL, Hyder F, Shulman RG . In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function. Annu Rev Physiol 2003; 65: 401–427.

    CAS  Article  Google Scholar 

  47. Behar KL, Rothman DL, Spencer DD, Petroff OA . Analysis of macromolecule resonances in 1H NMR spectra of human brain. Magn Reson Med 1994; 32: 294–302.

    CAS  Article  Google Scholar 

  48. Choi C, Coupland NJ, Hanstock CC, Ogilvie CJ, Higgins AC, Gheorghiu D et al. Brain gamma-aminobutyric acid measurement by proton double-quantum filtering with selective J rewinding. Magn Reson Med 2005; 54: 272–279.

    CAS  Article  Google Scholar 

  49. Straub RE, Lipska BK, Egan MF, Goldberg TE, Callicott JH, Mayhew MB et al. Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Mol Psychiatry 2007; 12: 854–869.

    CAS  Article  Google Scholar 

  50. Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S . Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 2004; 61: 300–308.

    CAS  Article  Google Scholar 

  51. Zhang ZJ, Reynolds GP . A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 2002; 55: 1–10.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A D Stan.

Ethics declarations

Competing interests

Dr Tamminga is or has been a deputy editor for the American Psychiatric Association; an ad hoc consultant for Astellas, Eli Lilly and Lundbeck; a council member for the Brain & Behavior Research Foundation, the Institute of Medicine, the National Alliance on Mental Illness and the National Institute of Mental Health; an organizer for the International Congress on Schizophrenia Research; a consultant for Kaye Scholer; and a member of the advisory board of drug development for Intra-Cellular Therapies. The other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Stan, A., Ghose, S., Zhao, C. et al. Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia. Mol Psychiatry 20, 433–439 (2015). https://doi.org/10.1038/mp.2014.54

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2014.54

This article is cited by

Search

Quick links