Prenatal Exposure to Histone Deacetylase Inhibitors Affects Gene Expression of Autism-Related Molecules and Delays Neuronal Maturation
Prenatal Exposure to Histone Deacetylase Inhibitors Affects Gene Expression of Autism-Related Molecules and Delays Neuronal Maturation
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DOI：
10.1007/s11064-016-1969-y
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发表时间：
2016-10-01
影响因子：
4.4
通讯作者：
Takuma, Kazuhiro
中科院分区：
文献类型：
--
作者：
Kawanai, Takuya;Ago, Yukio;Takuma, Kazuhiro
丙戊酸(VPA)是一种多靶点药物，是组蛋白脱乙酰酶(HDAC)的抑制剂。我们之前已经证明，产前暴露于胚胎12.5天(E12.5)的VPA，而不是E14.5天的VPA，会导致雄性小鼠后代出现自闭症样行为异常。我们还发现，出生前暴露于VPA会导致胚胎大脑中一过性的组蛋白超乙酰化，随后出生后前额叶和躯体感觉皮质的神经细胞数量减少。在目前的研究中，我们研究了产前抑制HDAC是否影响原代小鼠皮质神经元的神经元成熟。妊娠12.5天或14.5天，给予VPA(500 mg/kg)和选择性更高的HDAC抑制剂曲古抑素A(TSA；500Aµg/kg)，取胚胎大脑皮层进行原代神经元培养。出生前暴露于E12.5的VPA，而不是E14.5的VPA，减少了体外培养14天的神经元树突的总数、总长度和复杂性。VPA的作用在21DIV时减弱。在E12.5，而不是E14.5，暴露于TSA也延迟了皮质神经元的成熟。此外，实时定量聚合酶链式反应显示，产前暴露于TSA可降低神经连接蛋白-1(NLGN1)、SHANK2和Shank3的mRNA水平，而增加Contact-Association Protein-like 2mRNA的水平。在NLGN1-基因敲除细胞中也观察到了神经元成熟的延迟，这些细胞被转染了NLGN1 siRNA。这些发现表明，产前抑制HDAC会导致自闭症相关分子基因表达的变化，这些分子与神经元成熟延迟有关。
Valproic acid (VPA) is a multi-target drug and an inhibitor of histone deacetylase (HDAC). We have previously demonstrated that prenatal exposure to VPA at embryonic day 12.5 (E12.5), but not at E14.5, causes autism-like behavioral abnormalities in male mouse offspring. We have also found that prenatal VPA exposure causes transient histone hyperacetylation in the embryonic brain, followed by decreased neuronal cell numbers in the prefrontal and somatosensory cortices after birth. In the present study, we examined whether prenatal HDAC inhibition affects neuronal maturation in primary mouse cortical neurons. Pregnant mice were injected intraperitoneally with VPA (500 mg/kg) and the more selective HDAC inhibitor trichostatin A (TSA; 500 A mu g/kg) at E12.5 or E14.5, and primary neuronal cultures were prepared from the cerebral cortices of their embryos. Prenatal exposure to VPA at E12.5, but not at E14.5, decreased total number, total length, and complexity of neuronal dendrites at 14 days in vitro (DIV). The effects of VPA weakened at 21 DIV. Exposure to TSA at E12.5, but not at E14.5, also delayed maturation of cortical neurons. In addition, real-time quantitative PCR revealed that the prenatal exposure to TSA decreased neuroligin-1 (Nlgn1), Shank2, and Shank3 mRNA levels and increased contactin-associated protein-like 2 mRNA level. The delay in neuronal maturation was also observed in Nlgn1-knockdown cells, which were transfected with Nlgn1 siRNA. These findings suggest that prenatal HDAC inhibition causes changes in gene expression of autism-related molecules linked to a delay of neuronal maturation.