| Autor: |
Stan AD; Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA., Ghose S; Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA., Zhao C; Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA., Hulsey K; Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA., Mihalakos P; Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA., Yanagi M; Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA., Morris SU; UT Southwestern Medical School, currently at Baylor College of Medicine, Houston, TX, USA., Bartko JJ; Biostatistical Consultant, Newville, PA, USA., Choi C; Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, USA., Tamminga CA; Division of Translational Research in Schizophrenia, Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA. |
| Abstrakt: |
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. |
