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.
Highlights
Glial-dependent cerebrospinal fluid (CSF) flow through the brain parenchyma, by some termed the glymphatic system, facilitates the removal of waste by generating a convective flow of CSF and interstitial fluid [1,2]
The AQP4haplotypes were compared by means of dominant analysis, whereby 45 heterozygous subjects and 7 homozygotes were denoted as carriers of the minor allele (HtMi) and compared to 71 individuals homozygous for the major allele (HtMa) variant (S1 Data)
EEG quantification revealed that the HtMi carriers produced more slow wave energy (SWE) than the HtMa homozygotes (“genotype”: P < 0.03; Fig 2A), an effect paralleled by post hoc slow wave power analysis (S2 Fig)
Summary
Glial-dependent cerebrospinal fluid (CSF) flow through the brain parenchyma, by some termed the glymphatic system, facilitates the removal of waste by generating a convective flow of CSF and interstitial fluid [1,2]. Evidence suggests that the pathway relies on 3 main processes: Firstly, bulk flow of CSF through perivascular spaces is generated by arterial pulsations from the heartbeat and potentially to a lesser extent by pulsations from the respiration [3]. Movements of CSF from the perivascular space into the brain parenchyma relies on the water channel aquaporin 4 (AQP4), which is highly expressed on astrocytic vascular endfeet.
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