Reassessment of the involvement of Snord115 in the serotonin 2c receptor pathway in a genetically relevant mouse model.

Abstract

<i>SNORD115</i> has been proposed to promote the activity of serotonin (HTR2C) receptor via its ability to base pair with its pre-mRNA and regulate alternative RNA splicing and/or A-to-I RNA editing. Because <i>SNORD115</i> genes are deleted in most patients with the Prader-Willi syndrome (PWS), diminished HTR2C receptor activity could contribute to the impaired emotional response and/or compulsive overeating characteristic of this disease. In order to test this appealing but never demonstrated hypothesis in vivo, we created a CRISPR/Cas9-mediated <i>Snord115</i> knockout mouse. Surprisingly, we uncovered only modest region-specific alterations in <i>Htr2c</i> RNA editing profiles, while <i>Htr2c</i> alternative RNA splicing was unchanged. These subtle changes, whose functional relevance remains uncertain, were not accompanied by any discernible defects in anxio-depressive-like phenotypes. Energy balance and eating behavior were also normal, even after exposure to high-fat diet. Our study raises questions concerning the physiological role of <i>SNORD115</i>, notably its involvement in behavioural disturbance associated with PWS.