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5-HT2CR pre-RNA editing, alternate splicing and function in a mouse model of Prader-Willi syndrome

Doe, C., Garfield, A., Humby, Trevor, Relkovic, D., Wilkinson, Lawrence Stephen and Isles, Anthony Roger 2008. 5-HT2CR pre-RNA editing, alternate splicing and function in a mouse model of Prader-Willi syndrome. Fundamental & Clinical Pharmacology 22 (s2) , p. 125. 10.1111/j.1472-8206.2008.00601.x

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Abstract

Prader–Willi syndrome (PWS) is a complex genetic disorder caused by the loss of paternal gene expression from chromosome 15q11-q13. In addition to a number of coding genes, there are several imprinted small nucleolar (sno)RNAs present in the PWS cluster. Recent research has demonstrated that one of these, HBII-52, has a regulatory function in that it reduces alternate splicing of the RNA-editing region of the serotonin 2C receptor (5-HT2CR) pre-RNA, and that loss of expression of this snoRNA may lead to abnormal molecular processing of 5-HT2CR in the PWS brain. In turn, these molecular modifications of 5-HT2CR pre-RNA lead to a much less functional receptor. Using a mouse model of PWS (PWS-IC+/del) we are investigating the consequences of the loss of mbii-52 (mouse homologue of HBII-52) for 5- HT2CR functioning at a molecular, neurochemical and behavioural level. To achieve this we have examined the brains of adult PWS-IC+/del mice and found altered levels of expression and alternate splicing of 5-HT2CR. We are now examining RNA editing at five key sites of the 5-HT2CR pre-RNA. Behavioural studies, using a cohort of 64 mixed gender mice (28 PWS-IC +/del, 36 Wild Type (WT), weight range 19–65 g) are focussing on those known to be influenced by serotonin. These include spontaneous behaviours, such as marble burying and locomotor activity, and complex cognitive processes. PWS-IC+/del mice are hypoactive, but were no different to WT mice in the marble burying test. Importantly, marble burying behaviour was also not to be affected by dosing with the 5-HT2CR antagonist SB242084, demonstrating a degree of specificity of any 5- HT deficits in the PWS-IC+/del mice. We are now using the 5-choice serial reaction time test (5-csrtt) to examine aspects of attention and impulse control. The specificity of any deficits in the PWS-IC+/del mice and will be tested by examining the effects of pharmacological manipulations with 5-HT2CR and 5-HT2AR drugs. Our findings suggest that abnormalities in 5-HT2CR functioning may underlie aspects of the behavioural phenotype seen in PWS, and that the imprinted snoRNA mbii-52 plays an important role in sculpting brain and behaviour.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Psychology
Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information: SCP033 Special Issue: Abstracts of the EPHAR 2008 Congress, Manchester, UK, 13-17 July 2008
ISSN: 0767-3981
Last Modified: 03 May 2019 08:08
URI: http://orca.cf.ac.uk/id/eprint/5575

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