Satta R, Maloku E, Zhubi A, Pibiri F, Hajos M, Costa E, Guidotti A
Psychiatric Institute, Department of Psychiatry, University of Illinois, Chicago, IL 60612, USA.
Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16356-61. doi: 10.1073/pnas.0808699105. Epub 2008 Oct 13.
Tobacco smoking is frequently abused by schizophrenia patients (SZP). The major synaptically active component inhaled from cigarettes is nicotine, hence the smoking habit of SZP may represent an attempt to use nicotine self-medication to correct (i) a central nervous system nicotinic acetylcholine receptor (nAChR) dysfunction, (ii) DNA-methyltransferase 1 (DMT1) overexpression in GABAergic neurons, and (iii) the down-regulation of reelin and GAD(67) expression caused by the increase of DNMT1-mediated hypermethylation of promoters in GABAergic interneurons of the telencephalon. Nicotine (4.5-22 micromol/kg s.c., 4 injections during the 12-h light cycle for 4 days) decreases DNMT1 mRNA and protein and increases GAD(67) expression in the mouse frontal cortex (FC). This nicotine-induced decrease of DNMT1 mRNA expression is greater (80%) in laser microdissected FC layer I GABAergic neurons than in the whole FC (40%), suggesting selectivity differences for the specific nicotinic receptor populations expressed in GABAergic neurons of different cortical layers. The down-regulation of DNMT1 expression induced by nicotine in the FC is also observed in the hippocampus but not in striatal GABAergic neurons. Furthermore, these data show that in the FC, the same doses of nicotine that decrease DNMT1 expression also (i) diminished the level of cytosine-5-methylation in the GAD(67) promoter and (ii) prevented the methionine-induced hypermethylation of the same promoter. Pretreatment with mecamylamine (6 micromol/kg s.c.), an nAChR blocker that penetrates the blood-brain barrier, prevents the nicotine-induced decrease of FC DNMT1 expression. Taken together, these results suggest that nicotine, by activating nAChRs located on cortical or hippocampal GABAergic interneurons, can up-regulate GAD(67) expression via an epigenetic mechanism. Nicotine is not effective in striatal medium spiny GABAergic neurons that primarily express muscarinic receptors.
精神分裂症患者(SZP)经常有吸烟的陋习。从香烟中吸入的主要具有突触活性的成分是尼古丁,因此SZP的吸烟习惯可能代表一种通过尼古丁自我给药来纠正以下情况的尝试:(i)中枢神经系统烟碱型乙酰胆碱受体(nAChR)功能障碍;(ii)GABA能神经元中DNA甲基转移酶1(DMT1)的过表达;(iii)由于端脑GABA能中间神经元中启动子的DNMT1介导的高甲基化增加而导致的Reelin和GAD(67)表达下调。尼古丁(4.5 - 22微摩尔/千克,皮下注射,在12小时光照周期内分4次注射,共4天)可降低小鼠额叶皮质(FC)中DNMT1的mRNA和蛋白水平,并增加GAD(67)的表达。在激光显微切割的FC I层GABA能神经元中,这种尼古丁诱导的DNMT1 mRNA表达降低比在整个FC中(40%)更大(80%),这表明不同皮质层的GABA能神经元中表达的特定烟碱型受体群体存在选择性差异。在海马中也观察到尼古丁在FC中诱导的DNMT1表达下调,但在纹状体GABA能神经元中未观察到。此外,这些数据表明,在FC中,相同剂量的尼古丁在降低DNMT1表达时,还(i)降低了GAD(67)启动子中的胞嘧啶-5-甲基化水平,(ii)阻止了蛋氨酸诱导的同一启动子的高甲基化。用可穿透血脑屏障的nAChR阻滞剂美加明(6微摩尔/千克,皮下注射)预处理可阻止尼古丁诱导的FC中DNMT1表达降低。综上所述,这些结果表明,尼古丁通过激活位于皮质或海马GABA能中间神经元上的nAChRs,可通过一种表观遗传机制上调GAD(67)的表达。尼古丁对主要表达毒蕈碱受体的纹状体中等棘状GABA能神经元无效。