Journal
NATURE NEUROSCIENCE
Volume 20, Issue 9, Pages 1247-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/nn.4616
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Funding
- NIH [R01 MH084894, R01 MH111940, R01 MH104491, R01 MH086509, P50 MH096890, R21 MH103877, R01 MH090264, S10OD018522]
- Japan Society for the Promotion of Science (JSPS) [15H06719, 16K19786]
- MINECO/ERDF [SAF2009-08460, SAF2013-45084R]
- Dainippon Sumitomo Pharma
- NARSAD
- Basque Government [IT616-13]
- Basque Government
- JSPS [JSPS 23-3454]
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [16K19786, 15H06719] Funding Source: KAKEN
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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-kappa B in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-kappa B repressor I kappa B alpha. This upregulation of NF-kappa B 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-kappa B signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.
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