TY - JOUR
T1 - Antipsychotic-induced Hdac2 transcription via NF-ΰ B leads to synaptic and cognitive side effects
AU - Ibi, Daisuke
AU - De La Fuente Revenga, Mario
AU - Kezunovic, Nebojsa
AU - Muguruza, Carolina
AU - Saunders, Justin M.
AU - Gaitonde, Supriya A.
AU - Moreno, José L.
AU - Ijaz, Maryum K.
AU - Santosh, Vishaka
AU - Kozlenkov, Alexey
AU - Holloway, Terrell
AU - Seto, Jeremy
AU - Garciá-Bea, Aintzane
AU - Kurita, Mitsumasa
AU - Mosley, Grace E.
AU - Jiang, Yan
AU - Christoffel, Daniel J.
AU - Callado, Luis F.
AU - Russo, Scott J.
AU - Dracheva, Stella
AU - López-Giménez, Juan F.
AU - Ge, Yongchao
AU - Escalante, Carlos R.
AU - Meana, J. Javier
AU - Akbarian, Schahram
AU - Huntley, George W.
AU - González-Maeso, Javier
N1 - Funding Information:
The authors thank M. Fribourg, P. Roussos (Icahn School of Medicine at Mount Sinai), P. Bos, S. Bowers, A. Ellaithy (Virginia Commonwealth University School of Medicine), A. Gallitano (The University of Arizona), T. Nabeshima (Fujita Health University), M. Hiramatsu (Meijo University) and K. Yamada (Nagoya University) for their critical review of the manuscript; F. Isoda and C. Mobbs for their help in promoter assays; A. Meredith for his help in evaluating immunohistological assays; S. Morgello and the Manhattan HIV Brain Bank for providing control brain cortex; H. Morishita (Icahn School of Medicine at Mount Sinai) for the donation of CaMKIIα-Cre mice; D. Benson (Icahn School of Medicine at Mount Sinai) for the generous gift of Neuro2A cells; K. Deisseroth (Stanford University) for providing the p2A construct; J. Gingrich (Columbia University) for the donation of 5-HT2A knockout mice; E. Olson (University of Texas Southwestern Medical Center), R. Bassel-Duby (University of Texas Southwestern Medical Center) and E. Nestler (Icahn School of Medicine at Mount Sinai) for their gift of loxP-flanked Hdac2 mice; K. Hideshima and A. Hojati for assistance with biochemical assays; and the staff members of the Basque Institute of Legal Medicine for their cooperation in the study. NIH R01 MH084894 (J.G.M.), NIH R01 MH111940 (J.G.M.), Dainippon Sumitomo Pharma (J.G.M.), NARSAD (J.G.M.), the Japan Society for the Promotion of Science (JSPS) 15H06719 and 16K19786 (D.I.), NIH R01 MH104491 (G.W.H.), NIH R01 MH086509 (S.A.), NIH P50 MH096890 (S.A.), MINECO/ ERDF SAF2009-08460 (J.J.M. and L.F.C.), SAF2013-45084R (J.J.M. and L.F.C.), Basque Government IT616-13 (J.J.M.), NIH R21 MH103877 (S.D.) and NIH R01 MH090264 (S.J.R.) participated in the funding of this study. RNA-seq analysis was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai and the NIH infrastructure grant S10OD018522. C.M. and A.G.B. were recipients of a postdoctoral and a predoctoral fellowship from the Basque Government, respectively. D.I. was a recipient of postdoctoral fellowships from JSPS (Young Scientists JSPS 23-3454) and the Uehara Memorial Foundation.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.
AB - Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.
UR - http://www.scopus.com/inward/record.url?scp=85028453997&partnerID=8YFLogxK
U2 - 10.1038/nn.4616
DO - 10.1038/nn.4616
M3 - Article
C2 - 28783139
AN - SCOPUS:85028453997
SN - 1097-6256
VL - 20
SP - 1247
EP - 1259
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 9
ER -