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Abstract: Prader–Willi Syndrome (PWS) is a neurodevelopmental genetic disorder caused by loss of expression of imprinted, paternally inherited genes on chromosome 15q11q13. This imprinted gene cluster has its homologous region on mouse chromosome 7C. The extremely well conserved synteny between the human and the murine regions gave origin to the generation of mouse models for PWS, which facilitated investigations of the role and function of single genes or gene clusters in the pathogenesis of this disease. In this review we will describe which mouse models have been generated so far and how they were developed; we will focus on the consequences of single genes’ (or gene clusters’) loss of expression on the phenotype, highlighting the similarities to the human PWS features. PWS mouse models have brought major improvements in our knowledge about this complex condition, although the mechanisms implicated in its pathogenesis still remain not fully understood. [Copyright &y& Elsevier]

• A lack of the gene cluster SNORD116 may be responsible for some aspects of PWS. • Heterozygous Snord116 mutation mice had learning and memory deficits in three assays. • Heterozygous deletions in Snord116 did not impair exploratory or motor abilities. • Snord116+/− model is a valuable preclinical tool for investigating PWS. 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. [ABSTRACT FROM AUTHOR]