Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by mutations affecting paternal chromosome 15q11-q13, and characterized by hypotonia, hyperphagia, impaired cognition, and behavioural problems. Psychotic illness is a challenging problem for individuals with PWS and has different rates of prevalence in distinct PWS genotypes. Previously, we demonstrated behavioural and cognitive endophenotypes of relevance to psychiatric illness in a mouse model for one of the associated PWS genotypes, namely PWS-IC, in which deletion of the imprinting centre leads to loss of paternally imprinted gene expression and over-expression of Ube3a. Here we examine the broader gene expression changes that are specific to the psychiatric endophenotypes seen in this model. To do this we compared the brain transcriptomic profile of the PWS-IC mouse to the PWS-cr model that carries a deletion of the PWS minimal critical interval spanning the snoRNA Snord116 and Ipw. Firstly, we examined the same behavioural and cognitive endophenotypes of relevance to psychiatric illness in the PWS-cr mice. Unlike the PWS-IC mice, PWS-cr exhibit no differences in locomotor activity, sensory-motor gating, and attention. RNA-seq analysis of neonatal whole brain tissue revealed a greater number of transcriptional changes between PWS-IC and wild-type littermates than between PWS-cr and wild-type littermates. Moreover, the differentially expressed genes in the PWS-IC brain were enriched for GWAS variants of episodes of psychotic illness but, interestingly, not schizophrenia. These data illustrate the molecular pathways that may underpin psychotic illness in PWS and have implications for potential therapeutic interventions.

普瑞德威利综合征 (PWS) 是一种由影响父本染色体 15q11-q13 的突变引起的神经发育障碍，其特征为肌张力低下、食欲亢进、认知受损和行为问题。精神病对于 PWS 患者来说是一个具有挑战性的问题，并且不同 PWS 基因型的患病率不同。此前，我们在小鼠模型中证明了与精神疾病相关的行为和认知内表型，其中一种相关的 PWS 基因型，即 PWS-IC，其中印记中心的删除导致父系印记基因表达的丧失和父系印记基因的过度表达。宇部3a。在这里，我们检查了该模型中所见的精神病内表型特有的更广泛的基因表达变化。为此，我们将 PWS-IC 小鼠的大脑转录组谱与 PWS-cr 模型进行了比较，该模型删除了跨越 snoRNA Snord116和Ipw的 PWS 最小关键区间。首先，我们检查了 PWS-cr 小鼠与精神疾病相关的相同行为和认知内表型。与 PWS-IC 小鼠不同，PWS-cr 在运动活动、感觉运动门控和注意力方面没有表现出差异。对新生儿全脑组织的 RNA-seq 分析显示，PWS-IC 和野生型同窝小鼠之间的转录变化数量多于 PWS-cr 和野生型同窝小鼠之间的转录变化。此外，PWS-IC 大脑中差异表达的基因在精神疾病发作的 GWAS 变异中富集，但有趣的是，在精神分裂症中却没有。这些数据说明了 PWS 精神病的分子途径，并对潜在的治疗干预措施具有影响。