CONTEXT: The hippocampus is strongly implicated in schizophrenia and, to a lesser degree, bipolar disorder. Proteomic investigations of the different regions of the hippocampus may help us to clarify the basis and the disease specificity of the changes. OBJECTIVE: To determine whether schizophrenia and bipolar disorder are associated with distinct patterns of differential protein expression in specific regions of the hippocampus. DESIGN, SETTING, AND PATIENTS: A postmortem comparative proteomic study, including validation of differential expression, was performed. Midhippocampus samples from well-matched groups of 20 subjects with schizophrenia, 20 subjects with bipolar disorder, and 20 control cases from the Stanley Medical Research Institute Array Collection were analyzed. MAIN OUTCOME MEASURES: We used laser-assisted microdissection to enrich for tissue from the hippocampal regions and 2-dimensional difference gel electrophoresis to compare protein profiles. Levels of differentially expressed proteins were confirmed by enzyme-linked immunosorbent assay and Western blotting. Hippocampi from haloperidol-treated mice were used to help discriminate drug-associated from disease-associated protein changes. RESULTS: Across all hippocampal regions, 108 protein spots in schizophrenia and 165 protein spots in bipolar disorder were differentially expressed compared with controls. Sixty-one proteins were differentially expressed in both disorders. One hundred fifty-two of these proteins were identified by mass spectrometry, and they implicated a range of different processes including cytoskeletal and metabolic functions. In both disorders, cornu ammonis regions 2 and 3 were affected to a significantly greater degree than other hippocampal regions. Additionally, numerous proteins showed expression changes in more than 1 region and more than 1 disorder. Validation work confirmed changes in septin 11 and in the expression of proteins involved in clathrin-mediated endocytosis in both schizophrenia and bipolar disorder. CONCLUSIONS: Overall, similar protein changes were observed in schizophrenia and bipolar disorder and for the first time indicate that the most prominent proteomic changes occur within the hippocampus in cornu ammonis regions 2 and 3. The cytoskeletal protein septin 11 and the cellular trafficking process of clathrin-mediated endocytosis are implicated by our study.
CONTEXT: The hippocampus is strongly implicated in schizophrenia and, to a lesser degree, bipolar disorder. Proteomic investigations of the different regions of the hippocampus may help us to clarify the basis and the disease specificity of the changes. OBJECTIVE: To determine whether schizophrenia and bipolar disorder are associated with distinct patterns of differential protein expression in specific regions of the hippocampus. DESIGN, SETTING, AND PATIENTS: A postmortem comparative proteomic study, including validation of differential expression, was performed. Midhippocampus samples from well-matched groups of 20 subjects with schizophrenia, 20 subjects with bipolar disorder, and 20 control cases from the Stanley Medical Research Institute Array Collection were analyzed. MAIN OUTCOME MEASURES: We used laser-assisted microdissection to enrich for tissue from the hippocampal regions and 2-dimensional difference gel electrophoresis to compare protein profiles. Levels of differentially expressed proteins were confirmed by enzyme-linked immunosorbent assay and Western blotting. Hippocampi from haloperidol-treated mice were used to help discriminate drug-associated from disease-associated protein changes. RESULTS: Across all hippocampal regions, 108 protein spots in schizophrenia and 165 protein spots in bipolar disorder were differentially expressed compared with controls. Sixty-one proteins were differentially expressed in both disorders. One hundred fifty-two of these proteins were identified by mass spectrometry, and they implicated a range of different processes including cytoskeletal and metabolic functions. In both disorders, cornu ammonis regions 2 and 3 were affected to a significantly greater degree than other hippocampal regions. Additionally, numerous proteins showed expression changes in more than 1 region and more than 1 disorder. Validation work confirmed changes in septin 11 and in the expression of proteins involved in clathrin-mediated endocytosis in both schizophrenia and bipolar disorder. CONCLUSIONS: Overall, similar protein changes were observed in schizophrenia and bipolar disorder and for the first time indicate that the most prominent proteomic changes occur within the hippocampus in cornu ammonis regions 2 and 3. The cytoskeletal protein septin 11 and the cellular trafficking process of clathrin-mediated endocytosis are implicated by our study.
Authors: Azmeraw T Amare; Klaus Oliver Schubert; Liping Hou; Scott R Clark; Sergi Papiol; Urs Heilbronner; Franziska Degenhardt; Fasil Tekola-Ayele; Yi-Hsiang Hsu; Tatyana Shekhtman; Mazda Adli; Nirmala Akula; Kazufumi Akiyama; Raffaella Ardau; Bárbara Arias; Jean-Michel Aubry; Lena Backlund; Abesh Kumar Bhattacharjee; Frank Bellivier; Antonio Benabarre; Susanne Bengesser; Joanna M Biernacka; Armin Birner; Clara Brichant-Petitjean; Pablo Cervantes; Hsi-Chung Chen; Caterina Chillotti; Sven Cichon; Cristiana Cruceanu; Piotr M Czerski; Nina Dalkner; Alexandre Dayer; Maria Del Zompo; J Raymond DePaulo; Bruno Étain; Peter Falkai; Andreas J Forstner; Louise Frisen; Mark A Frye; Janice M Fullerton; Sébastien Gard; Julie S Garnham; Fernando S Goes; Maria Grigoroiu-Serbanescu; Paul Grof; Ryota Hashimoto; Joanna Hauser; Stefan Herms; Per Hoffmann; Andrea Hofmann; Stephane Jamain; Esther Jiménez; Jean-Pierre Kahn; Layla Kassem; Po-Hsiu Kuo; Tadafumi Kato; John Kelsoe; Sarah Kittel-Schneider; Sebastian Kliwicki; Barbara König; Ichiro Kusumi; Gonzalo Laje; Mikael Landén; Catharina Lavebratt; Marion Leboyer; Susan G Leckband; Alfonso Tortorella; Mirko Manchia; Lina Martinsson; Michael J McCarthy; Susan McElroy; Francesc Colom; Marina Mitjans; Francis M Mondimore; Palmiero Monteleone; Caroline M Nievergelt; Markus M Nöthen; Tomas Novák; Claire O'Donovan; Norio Ozaki; Urban Ösby; Andrea Pfennig; James B Potash; Andreas Reif; Eva Reininghaus; Guy A Rouleau; Janusz K Rybakowski; Martin Schalling; Peter R Schofield; Barbara W Schweizer; Giovanni Severino; Paul D Shilling; Katzutaka Shimoda; Christian Simhandl; Claire M Slaney; Alessio Squassina; Thomas Stamm; Pavla Stopkova; Mario Maj; Gustavo Turecki; Eduard Vieta; Julia Volkert; Stephanie Witt; Adam Wright; Peter P Zandi; Philip B Mitchell; Michael Bauer; Martin Alda; Marcella Rietschel; Francis J McMahon; Thomas G Schulze; Bernhard T Baune Journal: JAMA Psychiatry Date: 2018-01-01 Impact factor: 21.596