Examining the Reversibility of Long-Term Behavioral Disruptions in Progeny of Maternal SSRI Exposure.
Examining the Reversibility of Long-Term Behavioral Disruptions in Progeny of Maternal SSRI Exposure.
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DOI：
10.1523/eneuro.0120-18.2018
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发表时间：
2018-07
期刊：
影响因子：
3.4
通讯作者：
Dougherty JD
中科院分区：
文献类型：
--
作者：
Maloney SE;Akula S;Rieger MA;McCullough KB;Chandler K;Corbett AM;McGowin AE;Dougherty JD
血清素能失调与许多精神疾病有关。血清素在神经发育过程中起着广泛的营养作用；因此，在发育过程中对该系统的扰动可能会增加神经发育障碍的风险。流行病学研究调查了妊娠期间选择性血清素再摄取抑制剂（SSRI）治疗与后代自闭症谱系障碍（ASD）风险增加之间的关系。从这些研究中尚不清楚ASD易感性是否纯粹与母亲的精神诊断有关，或者治疗是否会带来额外的风险。我们试图确定母亲单独或结合遗传易感背景的SSRI治疗是否足以诱导与ASD相关的后代行为破坏。我们在不同的妊娠期和哺乳期将C57BL/6J或Celf6 +/-小鼠暴露于氟西汀（FLX）中，并对后代进行了评估社会交际互动和重复性行为模式（包括感觉敏感性）的任务。我们证明了小狗的超声波发声（usv）和社会等级行为的改变，以及持久性行为和触觉超敏反应的显著减少。Celf6突变小鼠表现出社会交际缺陷和持久性行为，与FLX没有进一步的相互作用。成年期再次暴露于FLX可改善触觉过敏，但会加剧显性表型。这表明血清素水平的急性缺乏可能是对感官刺激的异常反应的基础，而社会变化则是由于社会回路发育的改变。这些发现表明，独立于母亲压力的母亲FLX治疗可以诱导哺乳动物后代的行为中断，从而有助于我们了解血清素系统的发育作用以及SSRI治疗在怀孕期间对后代的可能风险。
Serotonergic dysregulation is implicated in numerous psychiatric disorders. Serotonin plays widespread trophic roles during neurodevelopment; thus perturbations to this system during development may increase risk for neurodevelopmental disorders. Epidemiological studies have examined association between selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy and increased autism spectrum disorder (ASD) risk in offspring. It is unclear from these studies whether ASD susceptibility is purely related to maternal psychiatric diagnosis, or if treatment poses additional risk. We sought to determine whether maternal SSRI treatment alone or in combination with genetically vulnerable background was sufficient to induce offspring behavior disruptions relevant to ASD. We exposed C57BL/6J or Celf6 +/- mouse dams to fluoxetine (FLX) during different periods of gestation and lactation and characterized offspring on tasks assessing social communicative interaction and repetitive behavior patterns including sensory sensitivities. We demonstrate robust reductions in pup ultrasonic vocalizations (USVs) and alterations in social hierarchy behaviors, as well as perseverative behaviors and tactile hypersensitivity. Celf6 mutant mice demonstrate social communicative deficits and perseverative behaviors, without further interaction with FLX. FLX re-exposure in adulthood ameliorates the tactile hypersensitivity yet exacerbates the dominance phenotype. This suggests acute deficiencies in serotonin levels likely underlie the abnormal responses to sensory stimuli, while the social alterations are instead due to altered development of social circuits. These findings indicate maternal FLX treatment, independent of maternal stress, can induce behavioral disruptions in mammalian offspring, thus contributing to our understanding of the developmental role of the serotonin system and the possible risks to offspring of SSRI treatment during pregnancy.