Antipsychotic drugs remain the standard treatment for schizophrenia. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic drugs leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition are not known. Here Ibi and colleagues demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in mouse and human frontal cortex, an effect triggered via the 5-HT2A-receptor-dependent downregulation of NF-κB repressor IκBα. Augmented HDAC2 transcription appears to mediate the negative effects of antipsychotic treatment on synaptic remodeling and cognition since deletion of HDAC2 in forebrain pyramidal neurons prevented these effects. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. This information may aid development of therapeutic strategies to improve cognitive function after antipsychotic treatment.
Ibi D, de la Fuente Revenga M, Kezunovic N, Muguruza C, Saunders JM, Gaitonde SA, Moreno JL et al.: Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects. Nat Neurosci. Aug. 7, 2017 [Epub ahead of print; doi: 10.1038/nn.4616].