Age-specific impacts of nicotine and withdrawal on hippocampal neuregulin signalling.
Age-specific impacts of nicotine and withdrawal on hippocampal neuregulin signalling.
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DOI：
10.1111/ejn.15780
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发表时间：
2022-09
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在美国，吸烟仍然是可预防死亡的主要原因，87%的吸烟者在18岁之前就开始吸烟。开始吸烟的年龄是吸烟频率和成功戒烟的主要预测因素。与成年期开始吸烟的人相比，在青春期开始吸烟的人成为重度吸烟者的可能性是2.33倍，戒烟的可能性是后者的一半。此外，精神分裂症是一种与青春期神经发育改变有关的疾病状态，是吸烟状况的主要预测因素。精神分裂症患者的吸烟率在60%-90%之间。有趣的是，神经调节蛋白信号通路(NSP)在神经发育中发挥重要作用，与精神分裂症和尼古丁使用障碍有关。具体地说，神经调节蛋白3(Nrg3)和Erb-B2受体酪氨酸激酶4(ErbB4)的SNPs与戒烟结果和精神分裂症有关。在这里，我们研究了慢性尼古丁(18 mg/kg/天)和24小时戒断对成年(20周龄)和青少年(4周龄)小鼠海马区NSP基因表达的影响。我们发现，戒除慢性尼古丁后，成年小鼠海马区ERBB4mRNA的表达减少，而青春期小鼠海马区ERBB4蛋白的表达增加。在成人或青少年组中，Nrg3mRNA和蛋白的表达不受慢性尼古丁或戒断的影响，但与青少年组相比，成人戒断组的Nrg3mRNA和突触体蛋白的表达较低。这些结果突出了尼古丁戒断对NSP的特定年龄的影响，并可能有助于在青春期开始吸烟的吸烟者戒烟率较低和香烟消费量较高。强迫戒断的青春期小鼠Nrg3、Nrg3os、ErbB4的表达水平高于成年强迫戒断小鼠。一种已提出的年龄依赖机制，其中钙信号的减少减少了Nrg3的表达，但在戒断青少年中较高的Nrg3os mRNA表达阻止了Nrg3的降解，导致在戒断过程中与成人相比，突触体NRG3蛋白水平更高。增加的突触体NRG3与ErbB4结合，导致内吞作用，并影响下游信号，这可能导致吸烟青少年患情感障碍的风险增加。
Smoking remains the leading cause of preventable death in the United States, with 87% of smokers starting before the age of 18. Age of initiation is a major predictive factor for smoking frequency and successful smoking cessation. People who initiate smoking during adolescences are 2.33 times more likely to become heavy smokers and half as likely to quit compared to smokers who started during adulthood. Additionally, schizophrenia, a disease state linked to altered neurodevelopment during adolescence, is a major predictive factor for smoking status. Smoking rates among people suffering from schizophrenia are between 60–90%. Interestingly, the Neuregulin Signaling Pathway (NSP), which plays an important role in neurodevelopment, is implicated in both schizophrenia and nicotine use disorder. Specifically, SNPS in neuregulin 3 (Nrg3) and Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4) have been associated with smoking cessation outcomes and schizophrenia. Here, we examine the effects of chronic nicotine (18 mg/kg/day) and 24-hour withdrawal on NSP gene expression in the hippocampus of adult (20-week-old) and adolescent (4-week-old) mice. We show that withdrawal from chronic nicotine decreased the expression of Erbb4 mRNA in the hippocampus of the adult mice but increased the expression of cytosolic Erbb4 protein in adolescent mice. Nrg3 mRNA and protein expression was not altered by chronic nicotine or withdrawal in the adult or adolescent cohorts, but Nrg3 mRNA and synaptosomal protein expression was lower in the adult withdrawal group when compared to their adolescent counterparts. These results highlight the age specific effects of nicotine withdrawal on the NSP and may contribute to the lower quit rate and higher cigarette consumption of smokers who initiation during adolescences. Adolescent mice undergoing forced withdrawal had a higher Nrg3, Nrg3os, ErbB4 mRNA than adult mice undergoing forced withdrawal. A proposed age dependent mechanism where a decrease in Ca2+ signaling decreases Nrg3 expression, but a higher Nrg3os mRNA expression in the withdrawal adolescents prevents degradation of Nrg3 leading to a higher level of synaptosomal NRG3 protein during withdrawal compared to the adults. The increased synaptosomal NRG3 binds to ErbB4 causing an endocytosis and effects downstream signaling which may lead to the increased risk of affective disorder in adolescents who smoke.
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电子香烟尼古丁浓度与随后的香烟吸烟和青少年烟的关联。
影响因子：
26.1
作者：
Goldenson NI;Leventhal AM;Stone MD;McConnell RS;Barrington-Trimis JL
通讯作者：
Barrington-Trimis JL
影响因子：
16.2
作者：
Brinkmann, Bastian G.;Agarwal, Amit;Sereda, Michael W.;Garratt, Alistair N.;Mueller, Thomas;Wende, Hagen;Stassart, Ruth M.;Nawaz, Schanila;Humml, Christian;Velanac, Viktorija;Radyushkin, Konstantin;Goebbels, Sandra;Fischer, Tobias M.;Franklin, Robin J.;Lai, Cary;Ehrenreich, Hannelore;Birchmeier, Carmen;Schwab, Markus H.;Nave, Klaus Armin
通讯作者：
Nave, Klaus Armin
影响因子：
7.6
作者：
Andersen, SL;Teicher, MH
通讯作者：
Teicher, MH
影响因子：
8.2
作者：
Choleris, E;Thomas, AW;Prato, FS
通讯作者：
Prato, FS
影响因子：
4
作者：
Carteron, C;Ferrer-Montiel, A;Cabedo, H
通讯作者：
Cabedo, H