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

Molecular Psychiatry volume 20, pages 433–439 (2015)Cite this article

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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.

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Author notes

  1. A D Stan and S Ghose: These authors contributed equally to this work. Both authors did distinct and equal work on this project.

Authors and Affiliations

  1. Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA

    A D Stan, S Ghose, P Mihalakos, M Yanagi & C A Tamminga

  2. Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA

    C Zhao, K Hulsey & C Choi

  3. UT Southwestern Medical School, currently at Baylor College of Medicine, Houston, TX, USA

    S U Morris

  4. Biostatistical Consultant, Newville,, PA, USA

    J J Bartko

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  1. A D Stan
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Correspondence to A D Stan.

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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.

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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

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