1. Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects
- Author
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Yan Jiang, Carolina Muguruza, Daisuke Ibi, Carlos R. Escalante, Maryum K. Ijaz, Daniel J. Christoffel, Schahram Akbarian, Alexey Kozlenkov, Scott J. Russo, Nebojsa Kezunovic, Vishaka Santosh, Jeremy Seto, Javier González-Maeso, Terrell Holloway, Supriya A Gaitonde, Luis F. Callado, J. Javier Meana, Mario de la Fuente Revenga, José L. Moreno, Stella Dracheva, Mitsumasa Kurita, Grace E. Mosley, George W. Huntley, Juan F. López-Giménez, Aintzane García-Bea, Yongchao Ge, Justin M. Saunders, Japan Society for the Promotion of Science, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), European Commission, Eusko Jaurlaritza, Uehara Memorial Foundation for International Students, and Icahn School of Medicine at Mount Sinai
- Subjects
0301 basic medicine ,Male ,Transcriptional Activation ,Mice, 129 Strain ,medicine.medical_treatment ,Repressor ,Histone Deacetylase 2 ,Mice, Transgenic ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Animals ,Humans ,Antipsychotic ,Maze Learning ,Mice, Knockout ,General Neuroscience ,HEK 293 cells ,NF-kappa B ,NF-κB ,Frontal Lobe ,Mice, Inbred C57BL ,IκBα ,030104 developmental biology ,HEK293 Cells ,chemistry ,Synaptic plasticity ,Forebrain ,Synapses ,Psychology ,Cognition Disorders ,Neuroscience ,030217 neurology & neurosurgery ,Antipsychotic Agents - Abstract
Ibi, Daisuke et al., 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-HT-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., 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.
- Published
- 2017