title: Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia.
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.
authors.affiliation: Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Stan
authors.affiliation: Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ghose
authors.affiliation: Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hulsey
authors.affiliation: Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Mihalakos
authors.affiliation: Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yanagi
authors.affiliation: UT Southwestern Medical School, currently at Baylor College of Medicine, Houston, TX, USA.
authors.forename: S U
authors.initials: SU
authors.lastname: Morris
authors.affiliation: Biostatistical Consultant, Newville, PA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Bartko
authors.affiliation: Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Choi
authors.affiliation: Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Tamminga
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D011180:Postmortem Changes; D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000235:genetics; D012559:Schizophrenia / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D055815:Young Adult
chemical_list: C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D011522:Protons; D016194:Receptors, N-Methyl-D-Aspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; C000179:N-acetylaspartate