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Mutant Neuropeptide S Receptor Reduces Sleep Duration with Preserved Memory Consolidation Lijuan Xing, Guangsen Shi, Yulia Mostovoy, Nicholas W

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Mutant Neuropeptide S Receptor Reduces Sleep Duration with Preserved Memory Consolidation Lijuan Xing, Guangsen Shi, Yulia Mostovoy, Nicholas W SCIENCE TRANSLATIONAL MEDICINE | RESEARCH ARTICLE SLEEP Copyright © 2019 The Authors, some rights reserved; Mutant neuropeptide S receptor reduces sleep duration exclusive licensee American Association with preserved memory consolidation for the Advancement Lijuan Xing1*, Guangsen Shi1*, Yulia Mostovoy2, Nicholas W. Gentry1, Zenghua Fan1, of Science. No claim 1 2,3,4 5 1,4,6,7† 1,4,6,7† to original U.S. Thomas B. Mcmahon , Pui-Yan Kwok , Christopher R. Jones , Louis J. Ptáček , Ying-Hui Fu Government Works Sleep is a crucial physiological process for our survival and cognitive performance, yet the factors controlling hu- man sleep regulation remain poorly understood. Here, we identified a missense mutation in a G protein–coupled neuropeptide S receptor 1 (NPSR1) that is associated with a natural short sleep phenotype in humans. Mice carry- ing the homologous mutation exhibited less sleep time despite increased sleep pressure. These animals were also resistant to contextual memory deficits associated with sleep deprivation. In vivo, the mutant receptors showed Downloaded from increased sensitivity to neuropeptide S exogenous activation. These results suggest that the NPS/NPSR1 pathway might play a critical role in regulating human sleep duration and in the link between sleep homeostasis and mem- ory consolidation. INTRODUCTION In this study, we identified another FNSS family and report a http://stm.sciencemag.org/ Sleep remains a relatively understudied phenomenon, despite being mutation in the NPSR1 gene causing a short sleep phenotype. Neu- essential in some form to most vertebrate life. Although humans ropeptide S receptor 1 (NPSR1) is a G protein–coupled receptor spend about one-third of their lives in the sleep state, an under- whose cognate ligand, neuropeptide S (NPS), has been reported to standing and recognition of its importance for our well-being are modulate arousal and sleep behaviors (17). Administration of NPS severely lacking. Sleep of sufficient duration, continuity, and depth in mice increases wakefulness and hyperactivity (17). We recreated is necessary to maintain high cognitive performance during wake the putative FNSS mutation—NPSR1-Y206H—in mice and found and to prevent certain physiological changes that may predispose that those carrying the homologous mutation showed a short sleep individuals to many adverse health outcomes (1–6). On average, phenotype similar to human FNSS. Further, they appeared to be at University of Washington on October 16, 2019 people require about 8 to 8½ hours of sleep each day to function resistant to certain memory deficits associated with sleep deprivation optimally (7). However, current surveys indicate that 35 to 40% of (SD). Correspondingly, we showed the NPSR1-Y206H substitution the adult U.S. population sleeps less than 7 hours on weekday nights changed downstream signaling dynamics and neuron behaviors in (8), a duration known to lead to cumulative deficits in behavioral mouse brain in response to NPS treatment. These data suggest a alertness and vigilant attention (9). causative role for the NPSR1-Y206H mutation in the short sleep Sleep duration varies greatly (and appear to be normally distrib- phenotype and advance our understanding of the genetic players in uted in the general population) among individuals and are heavily human sleep variability with potential therapeutic implications. influenced by both genetic and environmental factors (10–15), making their investigation particularly challenging. The specific mechanisms underlying these differences are largely unknown, and RESULTS until the recent identification of the first human gene/mutation The NPSR1-Y206H mutation was found in one FNSS family linked to a short sleep duration trait, there was no knowledge re- In one of our identified FNSS families (K50226), the habitual total garding genetic contributions to short sleep in humans (16). People sleep time of two subjects was characterized (fig. S1, question- with this trait [familial natural short sleep (FNSS)] have a lifelong naires) to be much shorter (5.5 and 4.3 hours) than the average tendency to sleep only 4 to 6 hours per night while still feeling well optimal sleep duration in the general population (8 to 8 ½ hours) rested (16). Anecdotally, these individuals also do not seem to bear (Fig. 1A) (18). To pinpoint potential genetic drivers, we performed the greater load of comorbid disorders traditionally associated with whole exome sequencing of DNA samples from these two individ- chronically restricted sleep. Identification of human FNSS genes uals and identified a shared point mutation in the NPSR1 gene. presents an opportunity to study not only the genetics of human This mutation converts a tyrosine into a histidine at position 206 sleep dynamics but also the relationship between sleep homeostasis (Y206H) in both of the two known isoforms (NPSR1A and B). The and health. mutated residue is located in one of the highly conserved extracel- lular domains of NPSR1 (Fig. 1, B and C). NPSR1-Y206H is a rare 1 mutation not found in the Exome Aggregation Consortium data- Department of Neurology, University of California San Francisco, San Francisco, −6 CA 94143, USA. 2Cardiovascular Research Institute, University of California San base and with a frequency of 4.06 × 10 in the Genome Aggregation 3 Francisco, San Francisco, CA 94143, USA. Department of Dermatology, University database. NPS has been previously reported to promote arousal in of California San Francisco, San Francisco, CA 94143, USA. 4Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA. rodents (17). Moreover, a homozygous NPSR1-N107I polymor- 5Department of Neurology, University of Utah, Salt Lake City, UT 84108, USA. 6Weill phism (Fig. 1C) was reported to be associated with slightly reduced Institute for Neurosciences, University of California San Francisco, San Francisco, 7 (~20 min) sleep duration in the human population by genetic asso- CA 94143, USA. Kavli Institute for Fundamental Neuroscience, University of California ciation studies (19, 20). Together, these data support the possibility San Francisco, San Francisco, CA 94143, USA. *These authors contributed equally to this work. that this mutation may be causal for the FNSS trait in affected †Corresponding author. Email: [email protected] (L.J.P.); [email protected] (Y.-H.F.) individuals. Xing et al., Sci. Transl. Med. 11, eaax2014 (2019) 16 October 2019 1 of 11 SCIENCE TRANSLATIONAL MEDICINE | RESEARCH ARTICLE A K50226 C N107I (P = 0.0132) (fig. S4, A and B). Npsr1-Y206H mice also showed N Y206H fewer episodes of NREM/REM sleep than WT (fig. S4, C and E), Y/H whereas the mean duration of each NREM/REM episode was un- *101371 (5.5 hours) changed (fig. S4, D and F). Together, these results suggest that 1 23 4 5 67 the NPSR1-Y206H mutation contributes to shorter sleep duration through a combination of longer average wake-bout length with Y/H lower wake-bout number and reduced number of REM/NREM bouts *101370 (4.3 hours) C with unchanged bout length. B TM4 Extracellular (186–212) TM5 (213–233) mice sustain higher sleep pressure Human TLIIFGKRTLSNGEVQCWALWPDDSYWTPYMTIVAFLVYFIPLTIISIMYGIV Npsr1-Y206H Mouse TLIIFGKRTLSNGEVQCWALWPDDSYWTPYMTIVAFLVYFIPLAIISVIYGLV Sleep pressure in mammals increases concomitantly with wake Rat TLIIFGKRTLSNGEVQCWALWPDDSYWTPYMTIVAFLVYFIPLTIISVIYGLV time. Spectral analysis of EEG showed an increase in the delta range Dog TLIIFGKRKLPNGEVQCWALWPDDSYWTPYMTIVAFLVYFIPLTIISVIYAIV Chicken TLIIFGKRQLSNGEVQCWALWPDDSYWIPYMTVVAFLVYFIPLIIISVIYSIV (1 to 4 Hz) power during NREM sleep in Npsr1-Y206H mice (fig. Xenopus TFIIFGKLKLPNGEMQCWALWPDDSYWTPYMTIVALLVYFIPLIIISVIYFIV S5A), a feature classically associated with increased sleep need. We Downloaded from TLIIFGKRQLSNGEVQCWAVWPDDSYWIPYMTTVAFLVYFIPLIIISVIYFIV Lizard next compared EEG delta power during NREM sleep across the Y > H light-dark cycle between mutant and control mice. During the dark Fig. 1. mutation was identified in a natural short sleep family. NPSR1-Y206H phase, Npsr1-Y206H mice accumulated higher delta power than (A) Pedigree of the family (K50226) carrying the NPSR1 mutation. The self-reported total sleep time per 24-hour day of mutation carriers is indicated. (B) NPSR1-Y206H WT, possibly the result of increased wake time, which dissipates is localized to the extracellular domain between transmembrane domains 4 and 5 during the light phase (Fig. 2F). This result indicates that Npsr1-Y206H (TM4/5) and is highly conserved among vertebrate NPSR1 orthologs. (C) Schematic mice, although having reduced sleep time, can sustain higher sleep http://stm.sciencemag.org/ of the mutations (Y206H and N107I) in the extracellular loops of NPSR1. pressure. Recently, quantitative phosphoproteomic analysis was performed in sleep-deprived WT mice and the Sleepy mutant mouse models. Npsr1-Y206H mice show increased mobile time High sleep pressure was found to be associated with induction of Given the highly conserved protein sequence between mouse and cumulative phosphorylation of the brain proteome that dissipated human NPSR1 (fig. S2A), we generated an Npsr1-Y206H knock-in during sleep (22). We measured expression of these proteins, called mouse model using CRISPR-Cas9. Endogenous Npsr1 mRNA ex- sleep-need-index phosphoproteins (SNIPPs), in mutant and WT pression was comparable between wild-type (WT; Npsr1+/+) and NPSR1 mice as a correlate metric for sleep pressure. Phosphorylation at University of Washington on October 16, 2019 mutant (Npsr1+/m)
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