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-HT_2A-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.

中文翻译：

---

抗精神病药通过NF-κB诱导的Hdac2转录导致突触和认知副作用。

抗精神病药仍然是精神分裂症治疗的标准。尽管它们能有效治疗幻觉和妄想，但长期服用抗精神病药会导致精神分裂症患者和动物模型的认知功能障碍。这些负面影响认知的分子机制仍有待阐明。在这里，我们证明了慢性抗精神病药的暴露会增加小鼠和人类额叶皮层中NF-κB的核易位，这是通过5-HT _2A触发的贩运事件受体依赖性NF-κB阻遏物IκBα的下调。NF-κB活性的这种上调导致其在Hdac2启动子上的结合增加，从而增加Hdac2转录。HDAC2在前脑锥体神经元中的删除防止了抗精神病药物治疗对突触重塑和认知的负面影响。相反，病毒介导的NF-κB信号传导激活通过HDAC2降低了皮层突触的可塑性。总之，这些观察结果可能有助于制定治疗策略以改善精神分裂症的治疗结果。