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

2017; Nature Portfolio; Volume: 20; Issue: 9 Linguagem: Inglês

10.1038/nn.4616

1546-1726

Daisuke Ibi, Mario de la Fuente Revenga, Nebojsa Kezunovic, Carolina Muguruza, Justin M. Saunders, Supriya A. Gaitonde, José L. Moreno, Maryum K. Ijaz, Vishaka Santosh, Alexey Kozlenkov, Terrell Holloway, Jeremy Seto, Aintzane García‐Bea, Mitsumasa Kurita, Grace E. Mosley, Yan Jiang, Daniel J. Christoffel, Luís F. Callado, Scott J. Russo, Stella Dracheva, Juan F. López‐Giménez, Yongchao Ge, Carlos Escalante, J. Javier Meana, Schahram Akbarian, George W. Huntley, Javier González‐Maeso,

Tryptophan and brain disorders

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.