Date created: 2021-01-26 11:17 AM | Last Updated: 2024-02-28 12:08 PM

Category: Data

Description: Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by mutations affecting paternal chromosome 15q11-q13, 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 paternal 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. PWS-cr exhibit no differences in locomotor activity, sensory-motor gating and attention of relevance to psychotic illness, and previously seen in the PWS-IC mice. RNA-seq analysis of neonatal brain 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 PWS-IC brain were enriched for GWAS variants associated with episodes of psychotic illness but, interestingly, not schizophrenia. These data illustrate the molecular pathways that may underpin psychotic illness in PWS and have implication for potential therapeutic interventions.