Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3.
Acute sleep deprivation upregulates serotonin 2A receptors in the frontal cortex of mice via the immediate early gene Egr3.
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DOI：
10.1038/s41380-021-01390-w
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发表时间：
2022-03
影响因子：
11
通讯作者：
Gallitano, Amelia L.
中科院分区：
文献类型：
--
作者：
Zhao, Xiuli;Ozols, Annika B.;Meyers, Kimberly T.;Campbell, Janet;McBride, Andrew;Marballi, Ketan K.;Maple, Amanda M.;Raskin, Carren;Mishra, Abhinav;Noss, Serena M.;Beck, Kelsey L.;Khoshaba, Rami;Bhaskara, Amulya;Godbole, Meghna N.;Lish, James R.;Kang, Paul;Hu, Chengcheng;Palner, Mikael;Overgaard, Agnete;Knudsen, Gitte M.;Gallitano, Amelia L.
5-羟色胺 2A 受体 (5-HT2AR) 介导致幻药物的致幻作用，是用于治疗精神障碍的主要药物类别的关键目标。这些发现表明，5-HT2AR 功能障碍可能会导致精神分裂症的症状，精神分裂症是一种以知觉和认知障碍为特征的精神疾病。事实上，大量研究发现精神分裂症患者大脑中的 5-HT2AR 减少。然而，调节 5-HT2AR 表达的机制仍知之甚少。在这里，我们发现生理环境刺激（睡眠剥夺）会在短短 6-8 小时内显着上调小鼠额叶皮质中的 5-HT2AR 水平（分别针对 mRNA 和蛋白质）。这种诱导需要活性依赖性立即早期基因转录因子早期生长反应 3 (Egr3)，因为它不会发生在 Egr3 缺陷 (−/−) 小鼠中。通过染色质免疫沉淀，我们发现 EGR3 蛋白在体内额皮质中与 Htr2a（编码 5-HT2AR 的基因）启动子结合，并通过 Htr2a 启动子中的两个 EGR3 结合位点驱动体外报告基因构建体的表达。这些结果表明，EGR3 直接调节额叶皮层中 Htr2a 的表达和 5-HT2AR 水平，以响应生理刺激。对公开的死后基因表达数据的分析表明，与对照组相比，精神分裂症患者前额皮质中的 EGR3 和 HTR2A mRNA 均减少。这些发现共同表明了环境刺激改变大脑受体水平的机制，该机制可能介导精神疾病的症状和治疗。
Serotonin 2A receptors (5-HT2ARs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HT2ARs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HT2ARs are reduced in the brains of individuals with schizophrenia. However, the mechanisms that regulate 5-HT2AR expression remain poorly understood. Here we show that a physiologic environmental stimulus, sleep deprivation, significantly upregulates 5-HT2ARs levels in the mouse frontal cortex in as little as 6–8 hours (for mRNA and protein, respectively). This induction requires the activity-dependent immediate early gene transcription factor early growth response 3 (Egr3) as it does not occur in Egr3 deficient (−/−) mice. Using chromatin immunoprecipitation, we show that EGR3 protein binds to the promoter of Htr2a, the gene that encodes the 5-HT2ARs, in the frontal cortex in vivo, and drives expression of in vitro reporter constructs via two EGR3 binding sites in the Htr2a promoter. These results suggest that EGR3 directly regulates Htr2a expression, and 5-HT2ARs levels, in the frontal cortex in response to physiologic stimuli. Analysis of publicly available post-mortem gene expression data revealed that both EGR3 and HTR2A mRNA are reduced in the prefrontal cortex of schizophrenia patients compared to controls. Together these findings suggest a mechanism by which environmental stimuli alter levels of a brain receptor that may mediate the symptoms, and treatment, of mental illness.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
5.3
作者：
Bekinschtein, Pedro;Constanza Renner, Maria;Weisstaub, Noelia
通讯作者：
Weisstaub, Noelia
影响因子：
3.3
作者：
Glausier, J. R.;Lewis, D. A.
通讯作者：
Lewis, D. A.
自闭症谱系障碍（ASD）、精神分裂症和双相情感障碍中全转录组异构体水平失调
影响因子：
56.9
作者：
Gandal, Michael J.;Zhang, Pan;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.
DOI：
10.1176/appi.ajp.2020.20070968
发表时间：
2021-10-01
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Ferrarelli F
通讯作者：
Ferrarelli F