Early Pharmacotherapy Restores Neurogenesis and Cognitive Performance in the Ts65Dn Mouse Model for Down Syndrome
Early Pharmacotherapy Restores Neurogenesis and Cognitive Performance in the Ts65Dn Mouse Model for Down Syndrome
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DOI：
10.1523/jneurosci.0534-10.2010
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发表时间：
2010-06-30
影响因子：
5.3
通讯作者：
Bartesaghi, Renata
中科院分区：
文献类型：
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作者：
Bianchi, Patrizia;Ciani, Elisabetta;Bartesaghi, Renata
唐氏综合征（Down Syndrome，DS）是一种以智力障碍和脑萎缩为特征的遗传性疾病。广泛的神经发生障碍的胎儿和新生儿DS大脑的特点，强烈表明，这种缺陷可能是智力低下的一个主要决定因素。我们的目标是在DS小鼠模型中建立早期药物治疗是否能改善神经发生和认知行为。新生Ts 65 Dn小鼠从出生后第（P）3天至P15天用氟西汀治疗，氟西汀是一种抑制成年Ts 65 Dn小鼠中5-羟色胺（5-HT）再摄取并增加增殖的抗抑郁药（Clark等人，2006年）。在P15，它们接受BrdU注射，并在2小时或1个月后被杀死。结果显示，P15 Ts 65 Dn小鼠在海马齿状回、室管膜下区、纹状体和新皮质中具有明显的增殖缺陷，并且氟西汀完全挽救了增殖。在未经处理的P15 Ts 65 Dn小鼠的海马中，我们发现正常的5-HT水平，但5-HT 1A受体和脑源性神经营养因子（BDNF）的表达较低。在Ts 65 Dn小鼠中，氟西汀治疗恢复了5-HT 1A受体和BDNF的表达。停止治疗一个月后，Ts 65 Dn小鼠的齿状回中有更多的存活细胞，更多的细胞具有神经元表型，更多的增殖前体细胞，和更多的颗粒细胞。对这些动物进行了情境恐惧条件反射测试，这是一项依赖于校园的记忆任务，并表现出记忆性能的完全恢复。结果表明，在DS模型中，用人类可用的药物进行早期药物治疗可以纠正神经发生和行为障碍。
Down syndrome (DS) is a genetic pathology characterized by intellectual disability and brain hypotrophy. Widespread neurogenesis impairment characterizes the fetal and neonatal DS brain, strongly suggesting that this defect may be a major determinant of mental retardation. Our goal was to establish, in a mouse model for DS, whether early pharmacotherapy improves neurogenesis and cognitive behavior. Neonate Ts65Dn mice were treated from postnatal day (P) 3 to P15 with fluoxetine, an antidepressant that inhibits serotonin (5-HT) reuptake and increases proliferation in the adult Ts65Dn mouse (Clark et al., 2006). On P15, they received a BrdU injection and were killed after either 2 h or 1 month. Results showed that P15 Ts65Dn mice had notably defective proliferation in the hippocampal dentate gyrus, subventricular zone, striatum, and neocortex and that proliferation was completely rescued by fluoxetine. In the hippocampus of untreated P15 Ts65Dn mice, we found normal 5-HT levels but a lower expression of 5-HT1A receptors and brain-derived neurotrophic factor (BDNF). In Ts65Dn mice, fluoxetine treatment restored the expression of 5-HT1A receptors and BDNF. One month after cessation of treatment, there were more surviving cells in the dentate gyrus of Ts65Dn mice, more cells with a neuronal phenotype, more proliferating precursors, and more granule cells. These animals were tested for contextual fear conditioning, a hippocampus-dependent memory task, and exhibited a complete recovery of memory performance. Results show that early pharmacotherapy with a drug usable by humans can correct neurogenesis and behavioral impairment in a model for DS.