Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model
Prenatal pharmacotherapy rescues brain development in a Down's syndrome mouse model
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DOI：
10.1093/brain/awt340
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发表时间：
2014-02-01
期刊：
影响因子：
14.5
通讯作者：
Bartesaghi, Renata
中科院分区：
文献类型：
--
作者：
Guidi, Sandra;Stagni, Fiorenza;Bartesaghi, Renata
唐氏综合症是一种由21号染色体三体引起的高患病率遗传疾病（每700-1000例活产婴儿中有1例），智力障碍是唐氏综合症的一个严重致残特征。越来越多的证据表明，广泛存在的神经发生障碍是大脑发育异常的主要决定因素，因此也是唐氏综合症中智力残疾的主要决定因素。这种缺陷会因树突萎缩和连通性改变而恶化。大多数旨在改善唐氏综合症认知能力的药物治疗都是在成年阶段的唐氏综合症小鼠模型中进行的。然而，由于神经发生主要是一个产前事件，旨在纠正唐氏综合症神经发生失败的治疗应该在怀孕期间进行。在大脑形成的最初阶段纠正神经发生可能反过来挽救不正确的大脑线路。我们研究的目的是确定是否有可能通过产前氟西汀药物治疗来挽救三体大脑特征的神经发育改变，氟西汀是一种能够恢复Ts65Dn唐氏综合征小鼠模型出生后海马神经发生的药物。妊娠Ts65Dn雌性小鼠从胚胎第10天起至分娩时服用氟西汀。在出生后第2天，幼鼠注射5-溴-2-脱氧尿嘧啶，并在2小时或43天后（45日龄）处死。未经治疗的2日龄Ts65Dn小鼠表现出严重的神经发生减少和细胞减少，整个前脑（室下区、颗粒下区、新皮层、纹状体、丘脑和下丘脑）、中脑（中脑）和后脑（小脑和脑桥）。在胚胎处理的2日龄Ts65Dn小鼠中，所有脑区域的前体细胞增殖和细胞结构都得到了完全恢复。经Ts65Dn处理的45日龄小鼠增殖能力和细胞数量仍有恢复。此外，胚胎处理恢复了树突发育、皮质和海马突触发育和脑容量。重要的是，这些影响伴随着行为表现的恢复。唐氏综合症引起的认知缺陷一直被认为是不可逆转的。目前的研究提供了新的证据，证明在胚胎发育期间使用氟西汀进行药物治疗能够完全挽救唐氏综合症典型的大脑发育异常和行为缺陷。如果氟西汀对小鼠大脑模型的积极作用在患有唐氏综合症的胎儿中得到复制，那么氟西汀这种可用于人类的药物可能代表着唐氏综合症智力残疾治疗的一个突破。
Intellectual impairment is a strongly disabling feature of Down's syndrome, a genetic disorder of high prevalence (1 in 700-1000 live births) caused by trisomy of chromosome 21. Accumulating evidence shows that widespread neurogenesis impairment is a major determinant of abnormal brain development and, hence, of intellectual disability in Down's syndrome. This defect is worsened by dendritic hypotrophy and connectivity alterations. Most of the pharmacotherapies designed to improve cognitive performance in Down's syndrome have been attempted in Down's syndrome mouse models during adult life stages. Yet, as neurogenesis is mainly a prenatal event, treatments aimed at correcting neurogenesis failure in Down's syndrome should be administered during pregnancy. Correction of neurogenesis during the very first stages of brain formation may, in turn, rescue improper brain wiring. The aim of our study was to establish whether it is possible to rescue the neurodevelopmental alterations that characterize the trisomic brain with a prenatal pharmacotherapy with fluoxetine, a drug that is able to restore post-natal hippocampal neurogenesis in the Ts65Dn mouse model of Down's syndrome. Pregnant Ts65Dn females were treated with fluoxetine from embryonic Day 10 until delivery. On post-natal Day 2 the pups received an injection of 5-bromo-2-deoxyuridine and were sacrificed after either 2 h or after 43 days (at the age of 45 days). Untreated 2-day-old Ts65Dn mice exhibited a severe neurogenesis reduction and hypocellularity throughout the forebrain (subventricular zone, subgranular zone, neocortex, striatum, thalamus and hypothalamus), midbrain (mesencephalon) and hindbrain (cerebellum and pons). In embryonically treated 2-day-old Ts65Dn mice, precursor proliferation and cellularity were fully restored throughout all brain regions. The recovery of proliferation potency and cellularity was still present in treated Ts65Dn 45-day-old mice. Moreover, embryonic treatment restored dendritic development, cortical and hippocampal synapse development and brain volume. Importantly, these effects were accompanied by recovery of behavioural performance. The cognitive deficits caused by Down's syndrome have long been considered irreversible. The current study provides novel evidence that a pharmacotherapy with fluoxetine during embryonic development is able to fully rescue the abnormal brain development and behavioural deficits that are typical of Down's syndrome. If the positive effects of fluoxetine on the brain of a mouse model are replicated in foetuses with Down's syndrome, fluoxetine, a drug usable in humans, may represent a breakthrough for the therapy of intellectual disability in Down's syndrome.