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bioRxiv · 10.1101/809822

The paternally imprinted gene Snord116 regulates cortical neuronal activity

Pace, M.·Colombi, I.·Falappa, M.·Freschi, A.·Bandarabadi, M.·Armirotti, A.·Encarnacion, B. M.·Adamantidis, A. R.·Roberto, A.·Cerri, M.·Chiappalone, M.·Tucci, V.
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Abstract

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder that is characterized by rapid eye movement (REM) sleep abnormalities. The disease is caused by genomic imprinting defects that are inherited through the paternal line. Among the genes located in the PWS region on chromosome 15 (15q11-q13), small nucleolar RNA 116 (Snord116) has been previously associated with intrusions of REM sleep into wakefulness in both humans and mice.\n\nHere, we further explore the processes of sleep regulation by studying the PWScrm+/p- mouse line, which carries a paternal deletion of Snord116. We focused on microstructural electrophysiological components of sleep, such as REM sleep features and sleep spindles within NREM sleep. While the former are thought to contribute to neuronal network formation early in brain development, the latter are markers of thalamocortical processes. Both signals are often compromised in neurodevelopmental disorders and influence functional properties of cortical neurons. Thus, we isolated and characterized the intrinsic activity of cortical neurons using in vitro microelectrode array (MEA) studies.\n\nOur results indicate that the Snord116 gene in mice selectively influences REM sleep properties, such as theta rhythms and the organization of REM episodes throughout sleep-wake cycles. Moreover, sleep spindles present specific abnormalities in PWS model systems, indicating that these features of sleep may translate as potential biomarkers in human PWS. We observed abnormalities in the synchronization of cortical neuronal activity that are accounted for by high levels of norepinephrine.\n\nIn conclusion, our results provide support for an important role of Snord116 in regulating brain activity during sleep and, in particular, cortical neuronal properties, thereby opening new avenues for developing interventions in PWS.\n\nSignificance StatementWe found that the Snord116 gene, a major player in Prader-Willi syndrome (PWS), significantly impacts REM sleep and its regulation. Additionally, we found that sleep spindles, a subtle electroencephalography (EEG) marker that occurs during NREM sleep, are dysregulated in PWS mice that carry a paternal deletion of the Snord116 gene. Using a combination of in vivo and in vitro experiments, we identified sleep features at the network and molecular level that suggest that Snord116 is fundamental in the synchronization of neuronal networks. Our study also provides a new pre-clinical tool to investigate the pathophysiology of sleep in PWS.

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Pace, M., Colombi, I., Falappa, M., Freschi, A., Bandarabadi, M., Armirotti, A., Encarnacion, B. M., Adamantidis, A. R., Roberto, A., Cerri, M., Chiappalone, M., Tucci, V.. 2019-10-17. The paternally imprinted gene Snord116 regulates cortical neuronal activity. https://doi.org/10.1101/809822

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