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

• Published in: Molecular psychiatry Vol. 20; no. 4; pp. 433 - 439
• Main Authors: Stan, A D, Ghose, S, Zhao, C, Hulsey, K, Mihalakos, P, Yanagi, M, Morris, S U, Bartko, J J, Choi, C, Tamminga, C A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2015; Nature Publishing Group
• Subjects: 59/57; 631/378; 64/60; 82/80; Adolescent; Adult; Animals; Aspartic Acid - analogs & derivatives; Aspartic Acid - metabolism; Autopsy; Behavioral Sciences; Biological Psychology; Brain research; Dentate gyrus; Dentate Gyrus - metabolism; Development and progression; Disease Models, Animal; GAD67 protein; Gene Expression Regulation; Glutamate; Glutamic Acid - metabolism; Health aspects; Hippocampus; Humans; Magnetic Resonance Spectroscopy; Medicine; Medicine & Public Health; Mental disorders; Methods; Mice; Mice, Knockout; Middle Aged; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Neurochemistry; Neurosciences; Neurotransmission; Nuclear magnetic resonance spectroscopy; original-article; Pharmacotherapy; Postmortem Changes; Proteins; Proton magnetic resonance; Protons; Psychiatry; Psychological aspects; Psychosis; Receptors, N-Methyl-D-Aspartate - deficiency; Receptors, N-Methyl-D-Aspartate - genetics; Resonance; Schizophrenia; Schizophrenia - pathology; Signal Transduction - physiology; Spectroscopy; Spectrum analysis; Tissues; Young Adult; γ-Aminobutyric acid; United States > US
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2014.54

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.