Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down syndrome: activation of β1-adrenergic receptor by xamoterol as a potential cognitive enhancer.
Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down syndrome: activation of β1-adrenergic receptor by xamoterol as a potential cognitive enhancer.
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DOI：
10.1016/j.nbd.2011.04.011
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发表时间：
2011-08
影响因子：
6.1
通讯作者：
Shamloo, Mehrdad
中科院分区：
文献类型：
--
作者：
Faizi, Mehrdad;Bader, Patrick L.;Tun, Christine;Encarnacion, Angelo;Kleschevnikov, Alexander;Belichenko, Pavel;Saw, Nay;Priestley, Matthew;Tsien, Richard W.;Mobley, William C.;Shamloo, Mehrdad
关键词：
唐氏综合症（DS）是人类遗传异常引起的最普遍的精神发育迟滞形式。这已在小鼠中成功建模，以产生Ts 65 Dn小鼠，这是DS的遗传模型。这种转基因小鼠模型与DS患者有许多身体和功能异常，包括神经元回路结构和功能的变化。在这些动物中检测到从蓝斑到海马的去甲肾上腺素能（NE能）传入的显著异常，以及NE能神经传递的缺陷。在目前的研究中，我们详细描述了Ts 65 Dn小鼠的行为表型，此外还使用药理学工具鉴定了介导DS模型中观察到的学习和记忆缺陷的靶受体。我们使用一系列标准和新颖的测试对小鼠表型进行了全面的研究，包括：i）运动（活动室、PhenoTyper和CatWalk），ii）学习和记忆（自发交替、延迟匹配位置水迷宫、恐惧条件反射和智力），以及iii）社会行为。Ts 65 Dn小鼠在新的和家庭笼环境中表现出增加的运动活动。在学习记忆测试中，包括自发交替、延迟匹配位置水迷宫、智力位置回避和情境恐惧条件反射，存在显著且可重复的缺陷。虽然Ts 65 Dn小鼠在3-chamber测试中没有表现出社交能力的缺陷，但检测到社交记忆明显受损。扎莫特罗是一种β1-肾上腺素能受体（β1-ADR）激动剂，能有效地恢复大鼠在情境恐惧条件反射、自发交替和新物体识别中的记忆缺陷。这些行为改善被选择性β1-ADR拮抗剂倍他洛尔逆转。总之，我们的研究结果表明，这种唐氏综合征小鼠模型显示认知障碍，这是由去甲肾上腺素能系统的失衡介导的。在这个唐氏综合征的实验模型中，β1-ADR的选择性激活确实恢复了一些这些行为缺陷。去甲肾上腺素能系统功能障碍及β1-ADR在认知功能障碍和DS发病机制中的作用有待进一步研究。恢复NE神经传递或选择性激活β1-ADR需要进一步研究，以开发任何潜在的治疗策略来缓解DS的记忆障碍症状。此外，由于去甲肾上腺素能系统显著参与心血管功能，因此需要进一步的安全性和转化研究，以确保该方法的安全性和有效性。
Down Syndrome (DS) is the most prevalent form of mental retardation caused by genetic abnormalities in humans. This has been successfully modeled in mice to generate the Ts65Dn mouse, a genetic model of DS. This transgenic mouse model shares a number of physical and functional abnormalities with people with DS, including changes in the structure and function of neuronal circuits. Significant abnormalities in noradrenergic (NE-ergic) afferents from the locus coeruleus to the hippocampus, as well as deficits in NE-ergic neurotransmission are detected in these animals. In the current study we characterized in detail the behavioral phenotype of Ts65Dn mice, in addition to using pharmacological tools for identification of target receptors mediating the learning and memory deficits observed in this model of DS. We undertook a comprehensive approach to mouse phenotyping using a battery of standard and novel tests encompassing: i) locomotion (Activity Chamber, PhenoTyper, and CatWalk), ii) learning and memory (spontaneous alternation, delayed matching-to-place water maze, fear conditioning, and Intellicage), and iii) social behavior. Ts65Dn mice showed increased locomotor activity in novel and home cage environments. There were significant and reproducible deficits in learning and memory tests including spontaneous alternation, delayed matching-to-place water maze, Intellicage place avoidance and contextual fear conditioning. Although Ts65Dn mice showed no deficit in sociability in the 3-chamber test, a marked impairment in social memory was detected. Xamoterol, a β1-adrenergic receptor (β1-ADR) agonist, effectively restored the memory deficit in contextual fear conditioning, spontaneous alternation and novel object recognition. These behavioral improvements were reversed by betaxolol, a selective β1-ADR antagonist. In conclusion, our results demonstrate that this mouse model of Down Syndrome display cognitive deficits which is mediated by imbalance in noradrenergic system. In this experimental model of Down Syndrome a selective activation of β1-ADR does restore some of these behavioral deficits. Further mechanistic studies will be needed to investigate the failure of noradrenergic system and the role of β1-ADR in cognitive deficit and pathogenesis of DS in people. Restoring NE neurotransmission or a selective activation of β1-ADR need to be further investigated for development of any potential therapeutic strategies for symptomatic relieve of memory deficit in DS. Furthermore, due to the significant involvement of noradrenergic system in the cardiovascular function further safety and translational studies will be needed to ensure the safety and efficacy of this approach.
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