Excessive Laughter-like Vocalizations, Microcephaly, and Translational Outcomes in the Ube3a Deletion Rat Model of Angelman Syndrome.
Excessive Laughter-like Vocalizations, Microcephaly, and Translational Outcomes in the Ube3a Deletion Rat Model of Angelman Syndrome.
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DOI：
10.1523/jneurosci.0925-21.2021
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发表时间：
2021-10-20
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影响因子：
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通讯作者：
Silverman JL
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文献类型：
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作者：
Berg EL;Jami SA;Petkova SP;Berz A;Fenton TA;Lerch JP;Segal DJ;Gray JA;Ellegood J;Wöhr M;Silverman JL
天使人综合症（AS）是一种罕见的遗传性神经发育障碍，其特征是智力障碍、运动和平衡缺陷、沟通障碍以及经常笑的快乐、兴奋的举止。我们试图阐明雄性和雌性大鼠的临床前结果测量，以解决AS和其他神经发育障碍的沟通异常，其中沟通不典型和/或缺乏语言是一个核心特征。我们在Ube3amat - /pat+ AS大鼠模型中发现并首次报道了过量的大笑样50 kHz超声发射，这表明其具有兴奋、顽皮的行为和升高的积极情绪，与AS个体的行为相似。同样与AS表型一致的是，Ube3amat - /pat+大鼠表现出与新伴侣的异常社会互动、明显的步态异常、认知受损、潜在的LTP缺陷和脑容量的严重减少。与目前可用的小鼠模型相比，这些独特的、健壮的表型提供了优势，并且将在评估as治疗方法的结果测量中具有很高的价值。安琪曼综合征（AS）是一种严重的神经遗传疾病，尽管几十年来一直使用小鼠模型进行研究，但目前尚无治愈方法。本研究使用最近开发的大鼠AS模型来描述疾病相关的结果措施，以促进治疗发展。我们发现大鼠是一个强有力的AS模型，与小鼠模型相比，它具有许多优势，表现出许多与AS相关的表型，包括过多的笑声样发声，海马LTP减少，以及整个大脑的体积异常。这些发现与有害的运动能力和背景压力无关，这些问题困扰着小鼠模型。该大鼠模型代表了AS领域的重要进展，本文报道的结果指标将成为治疗管道的核心。
Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor and balance deficits, impaired communication, and a happy, excitable demeanor with frequent laughter. We sought to elucidate a preclinical outcome measure in male and female rats that addressed communication abnormalities of AS and other neurodevelopmental disorders in which communication is atypical and/or lack of speech is a core feature. We discovered, and herein report for the first time, excessive laughter-like 50 kHz ultrasonic emissions in the Ube3amat–/pat+ rat model of AS, which suggests an excitable, playful demeanor and elevated positive affect, similar to the demeanor of individuals with AS. Also in line with the AS phenotype, Ube3amat–/pat+ rats demonstrated aberrant social interactions with a novel partner, distinctive gait abnormalities, impaired cognition, an underlying LTP deficit, and profound reductions in brain volume. These unique, robust phenotypes provide advantages compared with currently available mouse models and will be highly valuable as outcome measures in the evaluation of therapies for AS. SIGNIFICANCE STATEMENT Angelman syndrome (AS) is a severe neurogenetic disorder for which there is no cure, despite decades of research using mouse models. This study used a recently developed rat model of AS to delineate disease-relevant outcome measures to facilitate therapeutic development. We found the rat to be a strong model of AS, offering several advantages over mouse models by exhibiting numerous AS-relevant phenotypes, including overabundant laughter-like vocalizations, reduced hippocampal LTP, and volumetric anomalies across the brain. These findings are unconfounded by detrimental motor abilities and background strain, issues plaguing mouse models. This rat model represents an important advancement in the field of AS, and the outcome metrics reported herein will be central to the therapeutic pipeline.