Subscriber access provided by NEW YORK UNIV
Article
Expression of HDAC2 but not HDAC1 Transcript is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia Frederick A. Schroeder, Tonya M. Gilbert, Ningping Feng, Brendan D. Taillon, Nora D. Volkow, Robert B Innis, Jacob M. Hooker, and Barbara K. Lipska ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.6b00372 • Publication Date (Web): 28 Nov 2016 Downloaded from http://pubs.acs.org on November 28, 2016
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Chemical Neuroscience is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 22
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Chemical Neuroscience
Schroeder, p1 Title: Expression of HDAC2 but not HDAC1 Transcript is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia Author list and affiliations: Frederick A. Schroeder1*, Tonya M. Gilbert1, Ningping Feng2, Brendan D. Taillon1, Nora D. Volkow3, Robert B. Innis4, Jacob M. Hooker1, Barbara K. Lipska2 1. Athinoula A. Martinos Center, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 2. Human Brain Collection Core, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 3. National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 4. Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD * Corresponding author full contact details: Frederick A. Schroeder, Ph.D. Research Scientist Laboratory of Jacob M. Hooker, Ph.D. Athinoula A. Martinos Center for Biomedical Imaging Harvard Medical School | Massachusetts General Hospital Building 149 13th Street, Suite 2301 Charlestown, MA, USA, 02129
[email protected] (primary email) +001-410-664-1428 (office telephone, USA) Disclosures: The authors have no financial interest or conflicts of interest to report.
ACS Paragon Plus Environment
ACS Chemical Neuroscience
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 2 of 22
Schroeder, p2 Abstract: Objective: Postmortem brain studies support dysregulated expression of the histone deacetylase enzymes, HDAC1 and HDAC2, as a central feature in diseases including schizophrenia, bipolar disorder and depression. Our objective was to investigate HDAC expression in a large postmortem sample set representing healthy and disease brains. Methods: We used >700 well-characterized samples from patients diagnosed with schizophrenia (n=175), major depressive disorder (n=135) and bipolar disorder (n=61) to measure HDAC1 and HDAC2 transcript levels by quantitative real-time PCR in dorsolateral prefrontal cortex (DLPFC) and caudate compared to control samples. HDAC expression was calculated relative to the geometric mean of β-2-microglobulin, βglucuronidase, and β-actin. Results: In adult-age DLPFC, HDAC2 was decreased by 34% in schizophrenia samples compared to controls (p700 samples ranging from prenatal to 97 years of age to measure transcript expression by quantitative PCR and investigate effects of factors relevant in postmortem tissue research (age at death, tissue pH, RNA quality) and psychiatric disease (comorbidity of smoking, and therapeutic drug status).
Results and Discussion: HDAC2 levels are downregulated in DLPFC from schizophrenia samples and upregulated in major depressive disorder samples. Transcript levels of HDAC1 and HDAC2 were first measured by quantitative PCR in cDNA prepared from postmortem human DLPFC from brain donors without history of psychiatric illness (controls), and from patients diagnosed with SCZ, BP, or MDD; donor demographics and DLPFC sample details are shown in Table 1. For each transcript, relative expression was normalized to the geometric mean of three housekeeping genes; B2M, GUSB and ACTB. These normalizing genes were utilized on the basis of prior work in postmortem brain demonstrating favorable low variance16; relative quantification normalized to the geometric mean of three genes is a conservative and recommended method to reduce bias introduced by a single normalizing gene17.
Comparison of HDAC transcript levels from adult-age samples (≥ 18 years old) across psychiatric disease diagnosis groups revealed a significant difference of HDAC2 in the DLPFC with diagnosis as the primary factor (R2 = 0.21, p = 10-15). Posthoc testing revealed a statistically significant, 34% ANCOVA-corrected decrease in HDAC2 from SCZ samples compared to controls; F (3,566)=61.05, Tukey HSD p
