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.2020 May 5;18(5):e3000623.
doi: 10.1371/journal.pbio.3000623. eCollection 2020 May.

Haplotype of the astrocytic water channel AQP4 is associated with slow wave energy regulation in human NREM sleep

Affiliations

Haplotype of the astrocytic water channel AQP4 is associated with slow wave energy regulation in human NREM sleep

Sara Marie Ulv Larsen et al. PLoS Biol..

Abstract

Cerebrospinal fluid (CSF) flow through the brain parenchyma is facilitated by the astrocytic water channel aquaporin 4 (AQP4). Homeostatically regulated electroencephalographic (EEG) slow waves are a hallmark of deep non-rapid eye movement (NREM) sleep and have been implicated in the regulation of parenchymal CSF flow and brain clearance. The human AQP4 gene harbors several single nucleotide polymorphisms (SNPs) associated with AQP4 expression, brain-water homeostasis, and neurodegenerative diseases. To date, their role in sleep-wake regulation is unknown. To investigate whether functional variants in AQP4 modulate human sleep, nocturnal EEG recordings and cognitive performance were investigated in 123 healthy participants genotyped for a common eight-SNP AQP4-haplotype. We show that this AQP4-haplotype is associated with distinct modulations of NREM slow wave energy, strongest in early sleep and mirrored by changes in sleepiness and reaction times during extended wakefulness. The study provides the first human evidence for a link between AQP4, deep NREM sleep, and cognitive consequences of prolonged wakefulness.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Hypothesized role of the humanAQP4-haplotype investigated in a controlled sleep deprivation study.
(A) Based on the genetic modulation of AQP4 protein expression [22], we hypothesized that the high AQP4 expressing variant of theAQP4-haplotype (HtMa; black) presents with improved glymphatic flow compared to the low AQP4 expressing HtMi variant (red). Assuming that NREM slow waves are the endogenous regulator of glymphatic flow, the HtMa variant require less SWE to initiate glymphatic flow than the HtMi variant, establishing an innate glymphatic-sleep feedback loop. (B) Physical map of the AQP4 gene and the location of the 8 haplotype SNPs. The 3 SNPs genotyped in this sample are marked with full red arrows. Dark green blocks: coding exons; light blue blocks: 5′- and 3′-untranslated regions. (C) LD block among theAQP4 SNPs in the investigated haplotype. The pairwise LD coefficients (r2) of SNPs in the LD block are color-scaled in red tones with dark red indicating perfect LD (r2 = 1). (D) Table shows bases at the 8 different SNP locations in the AQP4 gene for the 2 haplotypes HtMa (76.7%) and HtMi (19.7%) and their respective frequencies in the CEU and TSI populations, representative of the investigated Swiss cohort. A total of 3.7% of CEU and TSI are predicted to be carriers of rare haplotype variants [23]. Frequencies in investigated study population were close to the prediction (HtMa: 75.7%; HtMi: 23.5; others: 0.7%; S1 Data). (E) Visualization of study design common for all subjects included from 6 separate studies. After a minimum 3-day inclusion period with monitored bedtimes and no caffeine intake, all study participants underwent an adaptation night in the laboratory before baseline sleep, 40 hours prolonged wakefulness and a recovery night, adding up to more than 1,950 hours (123 × 2 × 8 hours) of included sleep EEG recordings. Subjective sleepiness ratings and the approximately 10 min PVT were performed at 3-hour intervals. AQP4, aquaporin 4; CEU, Utah Residents from North and West Europe; EEG, electroencephalographic; HtMa, Major allele of haplotype; HtMi, Minor allele of haplotype; LD, linkage disequilibrium; NREM, non–rapid eye movement; PVT, psychomotor vigilance test; SNP, single nucleotide polymorphism; SWE, slow wave energy; TSI, Toscani in Italy;
Fig 2
Fig 2.AQP4-haplotype is associated with EEG energy regulation in the slow wave range.
Comparison of EEG energy (EEG power × time) across baseline and recovery nights in the slow wave range (0.75–4.5 Hz) within theAQP4 haplotype variants HtMa homozygotes (black) and HtMi carriers (red). To minimize false positive results, EEG data was analyzed by a hypothesis-driven fixed sequence procedure that only revealed significant effects of AQP4 in the whole-night slow wave band, which was significantly increased in theAQP4 HtMi-carrier group when compared to HtMa homozygotes (A; “genotype”: F1,121 = 5.0;P < 0.03; ηp2 = 3.95%). The effect was similar in baseline (B) and recovery (C) conditions and confined to the 0.75–2 Hz band. Inserts (B and C) represent full NREM sleep spectra for 0–20 Hz on log10 scale with gray shading indicating the slow wave band (S2 Data). Data represent mean ± SEM. By-bin unpaired two-tailedt tests: *P < 0.05, **P < 0.01. AQP4, aquaporin 4; EEG, electroencephalographic; HtMa, Major allele of haplotype; HtMi, Minor allele of haplotype; NREM, non–rapid eye movement.
Fig 3
Fig 3. Time course of EEG slow wave production is associated with theAQP4 haplotype.
To probe the role of AQP4 on sleep-wake regulation, SWE across the first 4 NREM episodes (A and B) was investigated. The data confirmed the previously detected overall increase in SWE in theAQP4 HtMi carriers (red) compared to the HtMa homozygote (black) group (“haplotype”: F1,121 = 5.39;P < 0.03, ηp2 = 4.26%). Moreover, a significant AQP4-haplotype modulation across the first 4 NREM episodes was observed (“haplotype x NREM episode”: F3,843 = 2.65;P < 0.05; ηp2 = 0.93%), an effect that was strongest in the second NREM episode. AQP4 HtMi carriers were found to have increased SWE mainly in the early part of the night (figure inserts). Spectral energy values of the slow wave band (0.75–4.5 Hz) in NREM sleep episodes 1 through 4 and the second part of the night (early: 1 and 2, late: 3 and 4) are plotted for the 2 haplotype groups for both baseline and recovery sleep (S3 Data). Data represent mean ± SEM. Unpaired two-tailedt tests: *P < 0.05, **P < 0.01. AQP4, aquaporin 4; EEG, electroencephalographic; HtMa, Major allele of haplotype; HtMi, Minor allele of haplotype; NREM, non–rapid eye movement; SWE, slow wave energy.
Fig 4
Fig 4. Objective and subjective measures of sleep deprivation is affected by theAQP4 haplotype.
Subjective sleepiness ratings on the SSS and objective alertness measures by the PVT. SSS scores (A), median speed (B), and attention lapses (C) on the PVT were quantified at 3-hour intervals across the 40 hours of prolonged wakefulness. Three-way linear mixed-model analysis revealed strong differences between day 1 and day 2 (“day”: Fall > 442,p < 0.0001) and moderate modulations of clock time (Fall > 4.6,p < 0.0005) and by the “day x clock time” interaction (Fall > 3.5,p < 0.004) in all 3 measures. Comparison of subjective sleepiness between the 71 HtMa homozygotes (black) and the 52 HtMi carriers (red) of theAQP4 haplotype revealed that the HtMi group coped slightly better with prolonged wakefulness than the HtMa homozygotes (“haplotype x day”: F1,364 = 4.5;P < 0.04; ηp2 = 1.22%; Panel A right). Intriguingly, theAQP4-haplotype dependent modulation of sleepiness was mirrored by a similar effect on PVT median speed performance among the 60 HtMa homozygotes and 44 HtMi carriers that were tested (“haplotype x day”: F1,1041 = 4.7;P < 0.04; ηp2 = 0.45%; Panel B right), an effect similar yet not significant for lapses of attention (“haplotype x day”: F1,1041 = 0.1,p > 0.78, Panel C right; S4 Data). Data represent estimated mean ± SEM. *p < 0.05 from the corresponding “haplotype x day” interaction. AQP4, aquaporin 4; hom: Homozygote; HtMa, Major allele of haplotype; HtMi, Minor allele of haplotype; PVT, psychomotor vigilance test; SSS, Stanford sleepiness scale.
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References

    1. Plog BA, Nedergaard M. The glymphatic system in CNS health and disease: past, present and future. Annu Rev Pathol. 2018. January 24;13:379–94. 10.1146/annurev-pathol-051217-111018 - DOI - PMC - PubMed
    1. Benveniste H, Lee H, Volkow ND. The Glymphatic Pathway. Neuroscientist. 2017. January 1;doi:1073858417691030 - PMC - PubMed
    1. Mestre H, Tithof J, Du T, Song W, Peng W, Sweeney AM, et al. Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nat Commun. 2018. 19;9(1):4878 10.1038/s41467-018-07318-3 - DOI - PMC - PubMed
    1. Mestre H, Hablitz LM, Xavier AL, Feng W, Zou W, Pu T, et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. Elife. 2018. 18;7. - PMC - PubMed
    1. Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA, Skare Ø, Laake P, et al. Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc Natl Acad Sci USA. 2011. October 25;108(43):17815–20. 10.1073/pnas.1110655108 - DOI - PMC - PubMed

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