Selective α4β2 Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons
Selective α4β2 Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons
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DOI：
10.1038/npp.2011.21
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发表时间：
2011-06-01
影响因子：
7.6
通讯作者：
Guidotti, Alessandro
中科院分区：
文献类型：
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作者：
Maloku, Ekrem;Kadriu, Bashkim;Guidotti, Alessandro
尼古丁改善了实验动物和人类受试者的认知能力和注意力，包括受神经精神疾病影响的患者。然而，尼古丁诱导的行为变化的具体分子机制仍不清楚。我们最近在小鼠中发现，重复注射尼古丁（其血浆浓度与高吸烟者中报告的浓度相当）导致表观遗传学诱导的谷氨酸脱羧酶67（GAD（67））表达增加。在这里，我们探讨了合成的α（4）β（2）和α（7）nAChR激动剂对GABA能表观遗传参数的影响。伐尼克兰（VAR），一种α（4）β（2）的高亲和力部分激动剂和α（7）神经元nAChR的低亲和力完全激动剂，以1-5 mg/kg/s.c.的剂量注射。每天2次，连续5天，引起皮质DNA甲基转移酶（DNMT）1 mRNA下降30-40%，GAD（67）mRNA和蛋白表达增加。这种GAD（67）的上调被nAChR拮抗剂美加明消除。此外，在给予VAR后，MeCP 2与GAD（67）启动子的结合水平显著降低。当VAR与美加明一起给药时，这种作用被消除。给予A-85380后，对皮质DNMT 1和GAD（67）表达的影响相似，A-85380是一种与α（4）β（2）结合的激动剂，但对含有nAChR的α（3）β（4）或α（7）亚型的亲和力可忽略不计。相比之下，PNU-282987（同聚体α（7）nAChR的激动剂）未能降低皮质DNMT 1 mRNA或诱导GAD（67）表达。目前的研究表明，α（4）β（2）nAChR激动剂可能比α（7）nAChR激动剂更适合于控制精神分裂症GABA能神经元的表观遗传学改变。Neuropsychopharmacology（2011）36，1366-1374; doi：10.1038/npp.2011.21; 2011年3月2日在线发表
Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic alpha(4)beta(2) and alpha(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at alpha(4)beta(2) and a lower affinity full agonist at alpha(7) neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP2 binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to alpha(4)beta(2) but has negligible affinity for alpha(3)beta(4) or alpha(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric alpha(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the alpha(4)beta(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the alpha(7) nAChR agonists. Neuropsychopharmacology (2011) 36, 1366-1374; doi:10.1038/npp.2011.21; published online 2 March 2011