0060 MCH Antagonism Improves Sleep-Wake Abnormalities in a Mouse Model of Prader-Willi Syndrome

Abstract Introduction Most individuals with Prader-Willi Syndrome (PWS) suffer from significant sleep-wake abnormalities, including excessive daytime sleepiness and high levels of rapid eye movement (REM) sleep. The neural basis for these sleep abnormalities in PWS remains unclear. Based on previous studies from our lab and others, we hypothesized that the overactivity of melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus contributes to sleep dysregulation in PWS. Methods 24-hour polysomnography followed by multiple sleep latency test was performed in order to determine the changes in spontaneous sleep-wake and sleepiness in Snord116del mice. Then to determine if higher MCH signaling contributes to sleep abnormalities in PWS, we a) examined any changes in MCH gene expression and MCH neuron counts in the lateral hypothalamus and b) studied the changes in sleep-wake following intraperitoneal injections of an MCHR1 antagonist. Results Snord116del mice exhibit excessive sleepiness and substantially higher REM sleep levels akin to PWS humans. MCH neurons and gene expression are normal in these mice, but MCH receptor-1 antagonist reversed these sleep abnormalities. Conclusion Snord116del mice are appropriate animal models for investigating sleep dysregulation in PWS and MCH antagonism may be an effective approach for treating or managing PWS sleep symptoms. Support (if any) Foundation for Prader-Willi Research (FPWR)