A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants.
A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants.
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DOI：
10.1186/s13229-018-0231-7
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发表时间：
2018
期刊：
影响因子：
6.2
通讯作者：
Elgersma Y
中科院分区：
文献类型：
--
作者：
Sonzogni M;Wallaard I;Santos SS;Kingma J;du Mee D;van Woerden GM;Elgersma Y
Angelman 综合征 (AS) 是一种由影响 UBE3A 功能的突变引起的神经发育障碍。 AS 的特点是智力障碍、运动协调受损、癫痫和行为异常，包括自闭症谱系障碍特征。 AS 治疗方法的开发在很大程度上依赖于在小鼠模型中测试药物疗效的能力，这些模型显示出可靠的、最好是临床相关的表型。我们之前描述了许多评估运动表现、重复行为、焦虑和癫痫易感性领域表型的行为范式。在这里，我们着手评估这些表型在标准化测试电池中进行测试时的稳健性。然后，我们使用这种行为测试电池来评估米诺环素和左旋多巴的疗效，这两种药物最近在 AS 临床试验中进行了测试。我们结合了八个独立实验的数据，涉及 111 只 Ube3a 小鼠和 120 只野生型同窝对照小鼠。通过荟萃分析，我们确定了子测试的统计功效以及假定的混杂因素的影响，例如性别和动物体重对转棒性能的影响。我们通过比较不同遗传背景下的 Ube3a 突变体以及比较独立衍生的 Ube3a 突变体系的行为表型，进一步评估了这些表型的稳健性。此外，我们还调查了测试电池是否允许重新测试相同的动物，这将允许受试者内的测试设计。我们发现测试组在不同的 Ube3a 突变体系中都很稳健，但证实并扩展了早期的研究，即几种表型对遗传背景非常敏感。我们进一步发现，听源性癫痫易感性表型在药物治疗后是完全可逆的，非常适合剂量探索研究。与临床试验结果一致，我们发现 Ube3a 小鼠的米诺环素和左旋多巴治疗在我们的测试电池中没有显示出任何性能改善的迹象。我们的研究为临床前药物测试提供了一个有用的工具，以确定天使综合征的治疗方法。由于在几个独立衍生的 Ube3a 系中观察到表型，因此测试组也可用于研究特定 Ube3a 突变对这些表型的影响。
Angelman syndrome (AS) is a neurodevelopmental disorder caused by mutations affecting UBE3A function. AS is characterized by intellectual disability, impaired motor coordination, epilepsy, and behavioral abnormalities including autism spectrum disorder features. The development of treatments for AS heavily relies on the ability to test the efficacy of drugs in mouse models that show reliable, and preferably clinically relevant, phenotypes. We previously described a number of behavioral paradigms that assess phenotypes in the domains of motor performance, repetitive behavior, anxiety, and seizure susceptibility. Here, we set out to evaluate the robustness of these phenotypes when tested in a standardized test battery. We then used this behavioral test battery to assess the efficacy of minocycline and levodopa, which were recently tested in clinical trials of AS. We combined data of eight independent experiments involving 111 Ube3a mice and 120 wild-type littermate control mice. Using a meta-analysis, we determined the statistical power of the subtests and the effect of putative confounding factors, such as the effect of sex and of animal weight on rotarod performance. We further assessed the robustness of these phenotypes by comparing Ube3a mutants in different genetic backgrounds and by comparing the behavioral phenotypes of independently derived Ube3a-mutant lines. In addition, we investigated if the test battery allowed re-testing the same animals, which would allow a within-subject testing design. We find that the test battery is robust across different Ube3a-mutant lines, but confirm and extend earlier studies that several phenotypes are very sensitive to genetic background. We further found that the audiogenic seizure susceptibility phenotype is fully reversible upon pharmacological treatment and highly suitable for dose-finding studies. In agreement with the clinical trial results, we found that minocycline and levodopa treatment of Ube3a mice did not show any sign of improved performance in our test battery. Our study provides a useful tool for preclinical drug testing to identify treatments for Angelman syndrome. Since the phenotypes are observed in several independently derived Ube3a lines, the test battery can also be employed to investigate the effect of specific Ube3a mutations on these phenotypes.
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影响因子：
2.9
作者：
Allensworth, Melody;Saha, Anand;Heck, Detlef H.
通讯作者：
Heck, Detlef H.
影响因子：
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作者：
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DOI：
10.1097/dbp.0b013e3181ee408e
发表时间：
2010-09-01
影响因子：
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作者：
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作者：
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通讯作者：
Beaudet AL
影响因子：
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作者：
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通讯作者：
Harbord, M