17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms
17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms
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DOI：
10.1186/s13229-018-0199-3
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发表时间：
2018-03-02
期刊：
影响因子：
6.2
通讯作者：
Schwaller, Beat
中科院分区：
文献类型：
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作者：
Filice, Federica;Lauber, Emanuel;Schwaller, Beat
背景：自闭症谱系障碍(ASD)是一组以两个核心症状为特征的神经发育障碍：社会交往和沟通障碍，以及受限、重复的行为和兴趣。由于过多的遗传和环境危险因素可能与ASD相关或导致ASD，ASD的病理生理学尚未完全了解。最近的发现表明，某些形式的ASD的一个可能的收敛途径可能是钙结合蛋白小白蛋白(PV)的下调。PV缺陷小鼠(PV-/-、PV+/-)，以及表现出与所有人类ASD核心症状相关的行为缺陷的Shank1-/-、Shank3-/-和VPA小鼠，都具有较低的PV表达水平。方法：基于17-β雌二醇(17-βestadiol，E2)可能增加PV表达的假设，从出生后5-15天开始给予E2治疗，并在出生后25-31天检测ASD相关行为。结果：E2治疗后PV表达水平显著增加，同时，PV+/-小鼠在直接互惠社会互动和三室社会接近试验中的社交能力缺陷以及重复行为都得到了减轻。对PV+/+小鼠进行E2治疗并没有增加PV水平，并且对社交和重复行为有不利影响。在PV-/-小鼠中，E2明显不影响PV水平；测试的行为与赋形剂处理的PV-/-小鼠没有不同。结论：我们的结果表明，类ASD行为的E2连锁改善仅发生在PV+/-小鼠身上，这表明在E2介导的ASD相关行为损害的救援中，PV上调是必需的。
Background: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by two core symptoms: impaired social interaction and communication, and restricted, repetitive behaviors and interests. The pathophysiology of ASD is not yet fully understood, due to a plethora of genetic and environmental risk factors that might be associated with or causal for ASD. Recent findings suggest that one putative convergent pathway for some forms of ASD might be the downregulation of the calcium-binding protein parvalbumin (PV). PV-deficient mice (PV-/-, PV+/-), as well as Shank1-/-, Shank3-/-, and VPA mice, which show behavioral deficits relevant to all human ASD core symptoms, are all characterized by lower PV expression levels.Methods: Based on the hypothesis that PV expression might be increased by 17-beta estradiol (E2), PV+/- mice were treated with E2 from postnatal days 5-15 and ASD-related behavior was tested between postnatal days 25 and 31.Results: PV expression levels were significantly increased after E2 treatment and, concomitantly, sociability deficits in PV+/- mice in the direct reciprocal social interaction and the 3-chamber social approach assay, as well as repetitive behaviors, were attenuated. E2 treatment of PV+/+ mice did not increase PV levels and had detrimental effects on sociability and repetitive behavior. In PV-/- mice, E2 obviously did not affect PV levels; tested behaviors were not different from the ones in vehicle-treated PV-/- mice.Conclusion: Our results suggest that the E2-linked amelioration of ASD-like behaviors is specifically occurring in PV+/- mice, indicating that PV upregulation is required for the E2-mediated rescue of ASD-relevant behavioral impairments.