Prader-Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition

Davies, Jennifer R. ORCID: https://orcid.org/0000-0001-7415-6129, Wilkinson, Lawrence S. ORCID: https://orcid.org/0000-0002-9337-6124, Isles, Anthony R. ORCID: https://orcid.org/0000-0002-7587-5712 and Humby, Trevor ORCID: https://orcid.org/0000-0002-1840-1799 2019. Prader-Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition. Human Molecular Genetics 28 (18) , pp. 3013-3023. 10.1093/hmg/ddz100

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Abstract

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13. In addition to endocrine and developmental issues, PWS presents with behavioural problems including stereotyped behaviour, impulsiveness and cognitive deficits. The PWS genetic interval contains several brain-expressed small nucleolar (sno)RNA species that are subject to genomic imprinting, including snord115 which negatively regulates post-transcriptional modification of the serotonin 2C receptor (5-HT2CR) pre-mRNA potentially leading to a reduction in 5-HT2CR function. Using the imprinting centre (IC) deletion mouse model for PWS (PWSICdel) we have previously shown impairments in a number of behaviours, some of which are abnormally sensitive to 5-HT2CR-selective drugs. In the stop-signal reaction time task test of impulsivity, PWSICdel mice showed increased impulsivity relative to wild-type littermates. Challenge with the selective 5-HT2CR agonist WAY163909 reduced impulsivity in PWSICdel mice but had no effect on wild-type behaviour. This behavioural dissociation in was also reflected in differential patterns of immunoreactivity of the immediate early gene c-Fos, with a blunted response to the drug in the orbitofrontal cortex of PWSICdel mice, but no difference in c-Fos activation in the nucleus accumbens. These findings suggest specific facets of response inhibition are impaired in PWSICdel mice and that abnormal 5-HT2CR function may mediate this dissociation. These data have implications for our understanding of the aetiology of PWS related behavioural traits and translational relevance for individuals with PWS who may seek to control appetite with the new obesity treatment 5-HT2CR agonist lorcaserin.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Psychology MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	This is an open access article distributed under the terms of the Creative Commons CC BY license.
Publisher:	Oxford University Press
ISSN:	0964-6906
Date of First Compliant Deposit:	10 May 2019
Date of Acceptance:	10 May 2019
Last Modified:	06 May 2023 23:16
URI:	https://orca.cardiff.ac.uk/id/eprint/122341

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