Prader–Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT(2C)R-mediated response inhibition

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 that negatively regulates post-transcriptional modification of the serotonin 2C receptor (5-HT(2C)R) pre-mRNA potentially leading to a reduction in 5-HT(2C)R function. Using the imprinting centre deletion mouse model for PWS (PWS(ICdel)) we have previously shown impairments in a number of behaviours, some of which are abnormally sensitive to 5-HT(2C)R-selective drugs. In the stop-signal reaction time task test of impulsivity, PWS(ICdel) mice showed increased impulsivity relative to wild-type (WT) littermates. Challenge with the selective 5-HT(2C)R agonist WAY163909 reduced impulsivity in PWS(ICdel) mice but had no effect on WT 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 PWS(ICdel) mice, but no difference in c-Fos activation in the nucleus accumbens. These findings suggest specific facets of response inhibition are impaired in PWS(ICdel) mice and that abnormal 5-HT(2C)R 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-HT(2C)R agonist lorcaserin.