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

作者：Ibi Daisuke; Revenga Mario de la Fuente; Kezunovic Nebojsa; Muguruza Carolina; Saunders Justin M; Gaitonde Supriya A; Moreno Jose L; Ijaz Maryum K; Santosh Vishaka; Kozlenkov Alexey; Holloway Terrell; Seto Jeremy; Garcia Bea Aintzane; Kurita Mitsumasa; Mosley Grace E; Jiang Yan; Christoffel Daniel J; Callado Luis F; Russo Scott J; Dracheva Stella; Lopez Gimenez Juan F; Ge Yongchao; Escalante Carlos R; Meana J Javier; Akbarian Schahram; Huntley George W

来源：Nature Neuroscience, 2017, 20(9): 1247-+.

DOI：10.1038/nn.4616

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.

• 出版日期2017-9