Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects.
Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects.
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DOI：
10.1038/nn.4616
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发表时间：
2017-09
影响因子：
25
通讯作者：
González-Maeso J
中科院分区：
文献类型：
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作者：
Ibi D;de la Fuente Revenga M;Kezunovic N;Muguruza C;Saunders JM;Gaitonde SA;Moreno JL;Ijaz MK;Santosh V;Kozlenkov A;Holloway T;Seto J;García-Bea A;Kurita M;Mosley GE;Jiang Y;Christoffel DJ;Callado LF;Russo SJ;Dracheva S;López-Giménez JF;Ge Y;Escalante CR;Meana JJ;Akbarian S;Huntley GW;González-Maeso J
抗精神病药物仍然是精神分裂症治疗的标准。尽管抗精神病药物在治疗幻觉和妄想方面有效，但长期接触抗精神病药物会导致精神分裂症患者和动物模型的认知缺陷。这些对认知的负面影响背后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物暴露增加了小鼠和人额叶皮质中NF-κB的核转位，这一转运事件是通过5-HT2A受体依赖的下调NF-κB抑制物IκBα而触发的。这种NF-κB活性的上调导致其与HDAC2启动子的结合增加，从而增强了HDAC2的转录。前脑锥体神经元中HDAC2的缺失阻止了抗精神病药物治疗对突触重构和认知的负面影响。相反，病毒介导的NF-κB信号的激活通过HDAC2降低了皮质突触的可塑性。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。
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.
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DOI：
10.1523/jneurosci.1758-09.2009
发表时间：
2009-09-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Covington HE 3rd;Maze I;LaPlant QC;Vialou VF;Ohnishi YN;Berton O;Fass DM;Renthal W;Rush AJ 3rd;Wu EY;Ghose S;Krishnan V;Russo SJ;Tamminga C;Haggarty SJ;Nestler EJ
通讯作者：
Nestler EJ
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
64.5
作者：
Gräff J;Joseph NF;Horn ME;Samiei A;Meng J;Seo J;Rei D;Bero AW;Phan TX;Wagner F;Holson E;Xu J;Sun J;Neve RL;Mach RH;Haggarty SJ;Tsai LH
通讯作者：
Tsai LH
影响因子：
25
作者：
Chen, Ying;Wang, Haibo;Yoon, Sung Ok;Xu, Xiaomei;Hottiger, Michael O.;Svaren, John;Nave, Klaus A.;Kim, Haesun A.;Olson, Eric N.;Lu, Q. Richard
通讯作者：
Lu, Q. Richard