Prader-Willi syndrome (PWS) is an imprinted neurodevelopmental disease caused by a loss of paternal genes on chromosome 15q11-q13. It is characterized by cognitive impairments, developmental delay, sleep abnormalities, and hyperphagia often leading to obesity. Clinical research has shown that a lack of expression of SNORD116, a paternally expressed imprinted gene cluster that encodes multiple copies of a small nucleolar RNA (snoRNA) in both humans and mice, is most likely responsible for many PWS symptoms seen in humans. The majority of previous research using PWS preclinical models focused on characterization of the hyperphagic and metabolic phenotypes. However, a crucial understudied clinical phenotype is cognitive impairments and thus we investigated the learning and memory abilities using a model of PWS, with a heterozygous deletion in Snord116. We utilized the novel object recognition task, which doesn't require external motivation, or exhaustive swim training. Automated findings were further confirmed with manual scoring by a highly trained blinded investigator. We discovered deficits in Snord116+/- mutant mice in the novel object recognition, location memory and tone cue fear conditioning assays when compared to age-, sex- matched, littermate control Snord116+/+ mice. Further, we confirmed that despite physical neo-natal developmental delays, Snord116+/- mice had normal exploratory and motor abilities. These results show that the Snord116+/- deletion murine model is a valuable preclinical model for investigating learning and memory impairments in individuals with PWS without common confounding phenotypes.

中文翻译：

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Prader-Willi 综合征 Snord116 缺失小鼠模型的认知缺陷。


普瑞德威利综合征 (PWS) 是一种印记性神经发育疾病，由染色体 15q11-q13 上的父系基因缺失引起。其特点是认知障碍、发育迟缓、睡眠异常和食欲过盛，通常会导致肥胖。临床研究表明，SNORD116（一种父系表达的印记基因簇，在人类和小鼠中编码小核仁 RNA (snoRNA) 的多个拷贝）的表达缺乏，很可能是人类中出现的许多 PWS 症状的原因。之前使用 PWS 临床前模型的大多数研究都集中在食欲旺盛和代谢表型的表征上。然而，一个重要的尚未研究的临床表型是认知障碍，因此我们使用 PWS 模型研究了学习和记忆能力，其中 Snord116 存在杂合缺失。我们利用了新颖的物体识别任务，该任务不需要外部动机或详尽的游泳训练。自动发现结果通过训练有素的盲法调查员的手动评分得到进一步证实。我们发现，与年龄、性别匹配的同窝对照 Snord116+/+ 小鼠相比，Snord116+/- 突变小鼠在新物体识别、位置记忆和音调线索恐惧条件实验中存在缺陷。此外，我们证实，尽管新生儿身体发育迟缓，Snord116+/- 小鼠仍具有正常的探索和运动能力。这些结果表明，Snord116+/- 缺失小鼠模型是一种有价值的临床前模型，可用于研究没有常见混杂表型的 PWS 个体的学习和记忆障碍。