Prenatal exposure to sodium valproate alters androgen receptor expression in the developing cerebellum in a region and age specific manner in male and female rats
Prenatal exposure to sodium valproate alters androgen receptor expression in the developing cerebellum in a region and age specific manner in male and female rats
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DOI：
10.1016/j.ijdevneu.2016.07.001
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发表时间：
2016-10-01
影响因子：
1.8
通讯作者：
Manzo, Jorge
中科院分区：
文献类型：
--
作者：
Perez-Pouchoulen, Miguel;Miquel, Marta;Manzo, Jorge
丙戊酸（VPA）是一种具有致畸活性的抗癫痫药物，与自闭症有关。在啮齿类动物中，子宫内暴露于VPA导致的大脑异常与自闭症患者的大脑异常相似。特别是，VPA减少了大鼠小脑中浦肯野神经元的数量，与自闭症中发现的小脑异常相似。因此，我们在胚胎第12天给怀孕雌性注射VPA （600 mg/kg, i.p）或0.9%生理盐水溶液，并在产后不同时间点从它们的后代身上获得小脑。睾丸激素与自闭症有关，在大脑发育过程中起着重要作用。因此，我们分别通过免疫组织化学和密度测定法对雄激素受体（AR）进行了鉴定和分析。我们发现VPA仅在PN7时降低了浦肯野浅层小脑小叶8的AR密度，而在PN14时与对照相比增加了AR密度。在雌性，VPA在PN14点降低了小脑6小叶表面浦肯野层的AR密度，但在同一时间点增加了小叶9的AR密度。在任何小脑小叶深浦肯野层的AR密度方面，男性和女性都没有发现差异。我们还发现，在大多数雄性小脑小叶的发育过程中，表层和深层区域的AR密度都在下降，但在雌性小脑小叶中，所有区域的AR密度都在下降。因此，我们的研究结果表明，VPA以特定年龄和区域的方式破坏雄性和雌性大鼠发育中的小脑的AR个体发生。未来的表观遗传学研究，包括对组蛋白去乙酰化酶（HDAC’s）的评估，可能会阐明这些结果，因为HDAC’s由浦肯野神经元表达，与AR相互作用，是VPA的靶点。这项工作有助于理解小脑的发育，并可能有助于理解小脑在自闭症等神经发育障碍中的作用。(c) 2016年。Elsevier Ltd.出版。版权所有。
Valproic acid (VPA) is an anti-epileptic drug with teratogenicity activity that has been related to autism. In rodents, exposure to VPA in utero leads to brain abnormalities similar than those reported in the autistic brain. Particularly, VPA reduces the number of Purkinje neurons in the rat cerebellum parallel to cerebellar abnormalities found in autism. Thus, we injected pregnant females on embryonic day 12 either with VPA (600 mg/kg, i.p.) or 0.9% saline solution and obtained the cerebellum from their offspring at different postnatal time points. Testosterone has been linked to autism and plays an important role during brain development. Therefore, we identified and analyzed the androgen receptor (AR) by immunohistochemistry and densitometry, respectively. We found VPA decreases AR density in the superficial Purkinje layer only in cerebellar lobule 8 at PN7, but increased it at PN14 compared to control in males. In females, VPA decreased AR density in the superficial Purkinje layer in cerebellar lobule 6 at PN14, but increased it in lobule 9 at the same time point. No differences were found in the deep Purkinje layer of any cerebellar lobule in terms of AR density neither in males nor females. We additionally found a particular AR density decreasing in both superficial and deep regions across development in the majority of cerebellar lobules in males, but in all cerebellar lobules in females. Thus, our results indicate that VPA disrupts the AR ontogeny in the developing cerebellum in an age and region specific manner in male and female rats. Future epigenetic studies including the evaluation of histone deacetylases (HDAC's) might shed light these results as HDAC's are expressed by Purkinje neurons, interact with the AR and are VPA targets. This work contributes to the understanding of the cerebellar development and it might help to understand the role of the cerebellum in neurodevelopmental disorders such as autism. (C) 2016 ISDN. Published by Elsevier Ltd. All rights reserved.