Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid.
Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid.
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DOI：
10.1016/j.stemcr.2015.10.012
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发表时间：
2015-12-08
影响因子：
5.9
通讯作者：
Nakashima K
中科院分区：
文献类型：
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作者：
Juliandi B;Tanemura K;Igarashi K;Tominaga T;Furukawa Y;Otsuka M;Moriyama N;Ikegami D;Abematsu M;Sanosaka T;Tsujimura K;Narita M;Kanno J;Nakashima K
据报告，产前暴露于丙戊酸（VPA）（一种已确定的抗癫痫药物）会损害接受VPA治疗的癫痫母亲所生儿童的出生后认知功能。然而，这些缺陷是如何产生的以及如何克服它们仍然是未知的。使用小鼠，我们发现，可比的出生后认知功能障碍很可能与胚胎神经发生的不合时宜的增强有关，这导致了神经前体细胞池的耗尽，从而降低了海马中成年神经发生的水平。此外，VPA处理小鼠的后代海马神经元显示异常的形态和活动。令人惊讶的是，这些损伤可以通过自愿跑步来改善。我们的研究表明，尽管产前暴露于VPA等抗癫痫药物可能会产生持续到成年的有害影响，但这些影响可能会被跑步等简单的身体活动所抵消。产前VPA治疗导致胚胎神经发生的过早增强产前VPA治疗具有损害成年神经发生的长期影响成年神经发生水平降低与认知功能障碍有关自愿跑步可以改善VPA引起的持续有害影响Nakashima及其同事表明，小鼠产前VPA暴露在癫痫母亲的儿童中产生了相当的出生后认知功能障碍。VPA增强胚胎神经发生，然后导致神经前体细胞池的耗竭，导致成年海马神经发生水平降低。他们进一步表明，自愿跑步可以恢复神经发生和恢复认知功能。
Prenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running. Prenatal VPA treatment caused an untimely enhancement of embryonic neurogenesis Prenatal VPA treatment has the long-term effect of impairing adult neurogenesis Reduced level of adult neurogenesis is associated with cognitive functional impairments Voluntary running can ameliorate the persistent detrimental effects caused by VPA Nakashima and colleagues show that prenatal VPA exposure in mice produced comparable postnatal cognitive functional impairments in children from epileptic mothers. VPA enhances embryonic neurogenesis, which then leads to depletion of the neural precursor cell pool, resulting in a decreased level of adult hippocampal neurogenesis. They further show that voluntary running could reinstate the neurogenesis and restore cognitive functions.