Loss of Snord115 mitigates Snord116-driven sleep abnormalities in mouse models of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by the loss of paternally expressed genes within the imprinted 15q11-q13 locus, which includes clusters of box C/D small nucleolar RNAs (SNORDs), notably the SNORD115 and SNORD116 gene families. Although SNORD116 deletions have been associated with sleep disturbances in patients and mouse models, the respective contributions of SNORD115 and SNORD116 to sleep regulation remain unclear. Here, we combined polysomnographic recordings and quantitative neuroanatomy to assess sleep-wake architecture, sleep homeostasis, and hypothalamic alterations in mice carrying paternal deletions of Snord115, Snord116, or both clusters. Snord116 deletion selectively increased REM sleep, particularly during the light phase and after sleep deprivation, without affecting slow-wave sleep or REM-associated theta activity. In contrast, Snord115 deletion alone did not alter sleep. Unexpectedly, combined Snord115/Snord116 deletion abolished the REM sleep phenotype observed in Snord116-deficient mice, indicating that Snord115 loss attenuates Snord116-dependent REM sleep alterations. Melanin-concentrating hormone (MCH) neuron density was reduced in Snord116-KO and double-KO mice, whereas hypocretin neurons were preserved across genotypes. However, REM sleep alterations did not parallel MCH neuron loss. Transcriptomic analyses revealed only limited hypothalamic gene expression changes. Together, these findings uncover an unexpected interaction between Snord115 and Snord116 in REM sleep regulation and highlight the complexity of modeling sleep dysfunctions associated with PWS.