Hara Yuta, Ago Yukio, Takano Erika, Hasebe Shigeru, Nakazawa Takanobu, Hashimoto Hitoshi, Matsuda Toshio, Takuma Kazuhiro
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 Japan.
Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 Japan.
Mol Autism. 2017 Jun 28;8:33. doi: 10.1186/s13229-017-0149-5. eCollection 2017.
MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain.
Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain.
These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure.
微小RNA是一类小的非编码RNA，在哺乳动物大脑中高度表达，微小RNA水平的失调可能与神经发育障碍如自闭症谱系障碍（ASD）有关。在本研究中，我们检测了产前丙戊酸（VPA）暴露是否会影响小鼠胚胎大脑中微小RNA的水平，尤其是脑特异性和富集的微小RNA。
在胚胎期第12.5天（E12.5）产前暴露于VPA可立即增加雄性胚胎大脑中miR-132的水平，但不影响miR-9或miR-124的水平。在E12.5产前暴露于VPA也可增加雌性胚胎大脑中miR-132的水平。我们进一步发现，在E12.5产前暴露于VPA会在miR-132表达之前增加雄性和雌性胚胎大脑中Arc、c-Fos和脑源性神经营养因子的mRNA水平。相比之下，在E14.5产前暴露于VPA对雄性或雌性胚胎大脑中的miR-132水平均无影响。在E12.5产前暴露于VPA还会降低甲基-CpG结合蛋白2和Rho GTP酶激活蛋白p250GAP的mRNA水平，这两者均为miR-132的分子靶点。此外，RNA序列分析显示，产前VPA暴露导致胚胎全脑中除miR-132外的几种微小RNA水平发生变化。
这些发现表明，胚胎期神经元活动依赖性微小RNA水平的改变，包括miR-132水平的升高，至少部分地是产前VPA暴露所产生的ASD样行为和皮质病理的基础。
