| Literature DB >> 28783139 |
Daisuke Ibi1,2,3, Mario de la Fuente Revenga1, Nebojsa Kezunovic4, Carolina Muguruza5,6, Justin M Saunders1, Supriya A Gaitonde1, José L Moreno1,2, Maryum K Ijaz1, Vishaka Santosh1, Alexey Kozlenkov2,7, Terrell Holloway2, Jeremy Seto2,8, Aintzane García-Bea2,5, Mitsumasa Kurita2, Grace E Mosley2, Yan Jiang2, Daniel J Christoffel4, Luis F Callado5,6,9, Scott J Russo4,10, Stella Dracheva2,7,10, Juan F López-Giménez1,11, Yongchao Ge12, Carlos R Escalante1, J Javier Meana5,6,9, Schahram Akbarian2,4,10, George W Huntley4,10, Javier González-Maeso1,2,10,12.
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.Entities:
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Year: 2017 PMID： 28783139 PMCID： PMC5675106 DOI： 10.1038/nn.4616
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884