Promoter IV-BDNF deficiency disturbs cholinergic gene expression of CHRNA5, CHRM2, and CHRM5: effects of drug and environmental treatments.
Promoter IV-BDNF deficiency disturbs cholinergic gene expression of CHRNA5, CHRM2, and CHRM5: effects of drug and environmental treatments.
复制标题
启动子 IV-BDNF 缺乏会干扰 CHRNA5、CHRM2 和 CHRM5 的胆碱能基因表达：药物和环境治疗的影响。
DOI：
10.1111/jnc.14129
复制
发表时间：
2017
影响因子：
4.7
通讯作者：
Overacre,AbigailE
中科院分区：
文献类型：
--
作者：
Sakata,Kazuko;Overacre,AbigailE
脑源性神经营养因子(BDNF)促进胆碱能神经元成熟。然而，依赖活性的BDNF表达如何影响特定的胆碱能基因表达仍不清楚。本研究通过检测启动子IV(KIV)和对照野生型小鼠体内活性依赖性BDNF缺陷小鼠的22个乙酰胆碱受体亚基、胆碱转运体(CHT)和胆碱乙酰转移酶(ChAT)的mRNA水平来解决这个问题。定量RT-PCR显示，与野生型小鼠相比，KIV小鼠额叶皮质和海马区烟碱型乙酰胆碱受体α5(CHRNA5)和海马型M5乙酰胆碱受体(CHRM5)表达显著降低，而M2型乙酰胆碱受体(CHRM2)表达显著增加。用氟西汀、苯乙肼、度洛西汀、丙咪嗪或强化环境治疗(EET)治疗3周后，这些基因的表达没有改变，只是EET只增加了KIV额叶皮质中CHRNA5的水平。EET也增加了CHRNA7、CHT和ChAT的水平，同样只在KIV额叶皮质中。在四种抗抑郁药中，丙咪嗪治疗最为显著；它上调了两种基因型鼠的海马CHRM2和额叶皮质CHRM5的表达，而仅上调了KIV小鼠的额叶皮质CHRNA7的表达。据我们所知，这是第一个BDNF缺乏干扰CHRNA5、CHRM2和CHRM5表达的证据。我们的结果表明，启动子IV-BDNF缺乏--发生在慢性应激下--通过这些受体导致胆碱能功能障碍。EET对CHRNA5是有效的，而针对CHRNA5、CHRM2和CHRM5的其他胆碱能基因或药物的代偿诱导可能成为逆转这些与BDNF相关的胆碱能功能障碍的替代策略。
Brain‐derived neurotrophic factor (BDNF) promotes maturation of cholinergic neurons. However, how activity‐dependent BDNF expression affects specific cholinergic gene expression remains unclear. This study addressed this question by determining mRNA levels of 22 acetylcholine receptor subunits, the choline transporter (CHT), and the choline acetyltransferase (ChAT) in mice deficient in activity‐dependent BDNF via promoter IV (KIV) and control wild‐type mice. Quantitative RT‐PCR revealed significant reductions in nicotinic acetylcholine receptor alpha 5 (CHRNA5) in the frontal cortex and hippocampus and M5 muscarinic acetylcholine receptor (CHRM5) in the hippocampus, but significant increases in M2 muscarinic acetylcholine receptor (CHRM2) in the frontal cortex of KIV mice compared to wild‐type mice. Three‐week treatments with fluoxetine, phenelzine, duloxetine, imipramine, or an enriched environment treatment (EET) did not affect the altered expression of these genes except that EET increased CHRNA5 levels only in KIV frontal cortex. EET also increased levels of CHRNA7, CHT, and ChAT, again only in the KIV frontal cortex. The imipramine treatment was most prominent among the four antidepressants; it up‐regulated hippocampal CHRM2 and frontal cortex CHRM5 in both genotypes, and frontal cortex CHRNA7 only in KIV mice. To the best of our knowledge, this is the first evidence that BDNF deficiency disturbs expression of CHRNA5, CHRM2, and CHRM5. Our results suggest that promoter IV‐BDNF deficiency – which occurs under chronic stress – causes cholinergic dysfunctions via these receptors. EET is effective on CHRNA5, while its compensatory induction of other cholinergic genes or drugs targeting CHRNA5, CHRM2, and CHRM5 may become an alternative strategy to reverse these BDNF‐linked cholinergic dysfunctions.