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Comparison of mouse models reveals a molecular distinction between psychotic illness in PWS and schizophrenia

Zahova, Simona, Humby, Trevor, Davies, Jennifer, Morgan, Joanne E. and Isles, Anthony 2021. Comparison of mouse models reveals a molecular distinction between psychotic illness in PWS and schizophrenia. Translational Psychiatry 11 , 433. 10.1038/s41398-021-01561-x

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Psychology
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Springer Nature [academic journals on nature.com]
ISSN: 2158-3188
Funders: MRC
Date of First Compliant Deposit: 10 August 2021
Date of Acceptance: 28 July 2021
Last Modified: 31 Jan 2022 07:40
URI: https://orca.cardiff.ac.uk/id/eprint/143275

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