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Nat Neurosci. 2017 Sep;20(9):1247-1259. doi: 10.1038/nn.4616. Epub 2017 Aug 7.

Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects.

Author information

1
Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
2
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
3
Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
4
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
5
Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, Spain.
6
Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, Leioa, Bizkaia, Spain.
7
James J. Peters Virginia Medical Center, Bronx, New York, USA.
8
Department of Biological Sciences, New York City College of Technology, Brooklyn, New York, USA.
9
BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain.
10
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
11
Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC-CSIC), Santander, Cantabria, Spain.
12
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Abstract

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.

PMID:
28783139
PMCID:
PMC5675106
DOI:
10.1038/nn.4616
[Indexed for MEDLINE]
Free PMC Article

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