Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition.
Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition.
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DOI：
10.3389/fnins.2016.00424
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发表时间：
2016
影响因子：
4.3
通讯作者：
Youn J
中科院分区：
文献类型：
--
作者：
Ellenbroek BA;August C;Youn J
有充分的证据表明，产前暴露于丙戊酸盐（或丙戊酸，VPA）会增加自闭症谱系障碍（ASD）的风险。与此相一致，单次注射VPA会在动物（如大鼠和小鼠）中诱导多种ASD样症状。然而，有同样强有力的证据表明，遗传因素对ASD的风险有显着影响，事实上，像大多数其他精神疾病一样，ASD现在通常被认为是遗传和环境因素之间相互作用的结果。鉴于VPA对肾上腺素能系统有显著影响，且5-羟色胺与ASD有很强的生化和遗传联系，我们旨在研究5-羟色胺转运蛋白遗传减少与产前丙戊酸盐给药之间的相互作用。更具体地说，我们在妊娠第12天（GD）将野生型（SERT+/+）大鼠和5-羟色胺转运蛋白缺失杂合子（SERT+/−）大鼠暴露于400 mg/kg VPA单次注射。成年后的后代在四个不同的测试中进行评估：高架加迷宫和新奇抑制喂养作为焦虑和前脉冲抑制（PPI）的措施和潜在抑制作为认知和信息处理的措施。结果表明，产前VPA显着增加焦虑的两个范例，降低PPI和减少条件反射的潜在抑制范例。然而，我们没有发现一个显着的基因-环境相互作用。我们认为这可能与VPA注射的时间有关，并表明GD 12可能是影响正常大鼠的最佳选择，而遗传受损的多巴胺能系统的大鼠可能在妊娠早期对VPA更敏感。总的来说，我们的数据是第一个研究基因 * 环境相互作用的遗传大鼠模型的ASD，并表明，时间可能是至关重要的长期结果。
There is ample evidence that prenatal exposure to valproate (or valproic acid, VPA) enhances the risk of developing Autism Spectrum Disorders (ASD). In line with this, a single injection of VPA induces a multitude of ASD-like symptoms in animals, such as rats and mice. However, there is equally strong evidence that genetic factors contribute significantly to the risk of ASD and indeed, like most other psychiatric disorders, ASD is now generally thought to results from an interaction between genetic and environmental factors. Given that VPA significantly impacts on the serotonergic system, and serotonin has strong biochemical and genetic links to ASD, we aimed to investigate the interaction between genetic reduction in the serotonin transporter and prenatal valproate administration. More specifically, we exposed both wildtype (SERT+/+) rats and rats heterozygous for the serotonin transporter deletion (SERT+/−) to a single injection of 400 mg/kg VPA at gestational day (GD) 12. The offspring, in adulthood, was assessed in four different tests: Elevated Plus Maze and Novelty Suppressed Feeding as measures for anxiety and prepulse inhibition (PPI) and latent inhibition as measures for cognition and information processing. The results show that prenatal VPA significantly increased anxiety in both paradigm, reduced PPI and reduced conditioning in the latent inhibition paradigm. However, we failed to find a significant gene–environment interaction. We propose that this may be related to the timing of the VPA injection and suggest that whereas GD12 might be optimal for affecting normal rat, rats with a genetically compromised serotonergic system may be more sensitive to VPA at earlier time points during gestation. Overall our data are the first to investigate gene * environmental interactions in a genetic rat model for ASD and suggest that timing may be of crucial importance to the long-term outcome.
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