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Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT 2C R) pre-RNA is negatively regulated by the small nucleolar RNA,  Snord115 , loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT 2C R in the regulation of ingestive behaviour we investigated the pathophysiological implications of  Snord115  deficiency on 5-HT 2C R regulated appetite in a genotypically relevant PWS mouse model (PWS-IC). Specifically, we demonstrate that loss of  Snord115  expression is associated with increased levels of hypothalamic truncated 5-HT 2C R pre-mRNA. The 5-HT 2C R promotes appetite suppression via engagement of the central melanocortin system.  Pro-opiomelancortin  ( Pomc ) mRNA levels within the arcuate nucleus of the hypothalamus (ARC) were reduced in PWS-IC mice. We then went on to assess the functional consequences of these molecular changes, demonstrating that PWS-IC mice are unresponsive to an anorectic doses of a 5-HT 2C R agonist and that this is associated with attenuated activation of POMC neurons within the ARC. These data provide new insight into the significance of  Htr2c  pre-mRNA processing to the physiological regulation of appetite and potentially the pathological manifestation of hyperphagia in PWS. Furthermore, these findings have translational relevance for individuals with PWS who may seek to control appetite with another 5-HT 2C R agonist, the new obesity treatment lorcaserin.   Electronic supplementary material  The online version of this article (doi:10.1186/s13041-016-0277-4) contains supplementary material, which is available to authorized users.

Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetite