Effect of early postnatal exposure to valproate on neurobehavioral development and regional BDNF expression in two strains of mice
Effect of early postnatal exposure to valproate on neurobehavioral development and regional BDNF expression in two strains of mice
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DOI：
10.1016/j.yebeh.2017.02.026
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发表时间：
2017-05-01
影响因子：
2.6
通讯作者：
Pimentel, Tiare
中科院分区：
文献类型：
--
作者：
Bath, Kevin G.;Pimentel, Tiare
丙戊酸作为癫痫的一线治疗药物已有 30 多年的历史。近年来，产前接触丙戊酸与致畸作用有关，限制了其在怀孕或育龄妇女中的使用。然而，尽管丙戊酸对发育有潜在的不利影响，但在一些国家，丙戊酸在儿科人群中的使用率仍然很高。动物模型使我们能够检验有关出生后丙戊酸暴露对神经行为发育的潜在影响的假设，并确定介导观察到的影响的潜在机制。在这里，我们测试了出生后早期（P4-P11）丙戊酸暴露（100 mg/kg 和 200 mg/kg）对两种品系小鼠（SVE129 和 C57B1/6N）运动和情感发育的影响。我们还评估了早期丙戊酸暴露对区域 BDNF 蛋白水平的影响，BDNF 蛋白水平是丙戊酸的潜在目标，也是神经发育结果的调节因子。我们发现生命早期接触丙戊酸会导致 SVE129 和 C57B1/6N 小鼠出现明显的运动障碍。两个品系的小鼠均表现出体重增加的显着延迟，以及翻正反射（P7-8）、钢丝悬挂（P17）、旷场（P12和P21）和旋转（P25和P45）任务的损伤。有趣的是，一些早期运动效应是应变和剂量依赖性的。我们观察到丙戊酸对焦虑样行为的早期标志没有影响。重要的是，生命早期接触丙戊酸对局部 BDNF 表达有显着影响，导致两种小鼠小脑中 BDNF 水平下降近 50%，但不影响海马 BDNF 蛋白水平。这些观察结果表明，出生后接触丙戊酸可能对神经和行为发育产生显着的、区域特异性的影响，并对小脑发育和运动功能产生特定的影响。 (C) 2017 Elsevier Inc. 保留所有权利。
Valproate has been used for over 30 years as a first-line treatment for epilepsy. In recent years, prenatal exposure to valproate has been associated with teratogenic effects, limiting its use in women that are pregnant or of childbearing age. However, despite its potential detrimental effects on development, valproate continues to be prescribed at high rates in pediatric populations in some countries. Animal models allow us to test hypotheses regarding the potential effects of postnatal valproate exposure on neurobehavioral development, as well as identify potential mechanisms mediating observed effects. Here, we tested the effect of early postnatal (P4-P11) valproate exposure (100 mg/kg and 200 mg/kg) on motor and affective development in two strains of mice, SVE129 and C57B1/6N. We also assessed the effect of early valproate exposure on regional BDNF protein levels, a potential target of valproate, and mediator of neurodevelopmental outcomes. We found that early life valproate exposure led to significant motor impairments in both SVE129 and C57B1/6N mice. Both lines of mice showed significant delays in weight gain, as well as impairments in the righting reflex (P7-8), wire hang (P17), open field (P12 and P21), and rotarod (P25 and P45) tasks. Interestingly, some of the early locomotor effects were strain and dose-dependent. We observed no effects of valproate on early markers of anxiety-like behavior. Importantly, early life valproate exposure had significant effects on regional BDNF expression, leading to a near 50% decrease in BDNF levels in the cerebellum of both strains of mice, while not impacting hippocampal BDNF protein levels. These observations indicate that postnatal exposure to valproate may have significant, and region-specific effects, on neural and behavioral development, with specific consequences for cerebellar development and motor function. (C) 2017 Elsevier Inc. All rights reserved.