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Sleep. 2019 Jul 13. pii: zsz161. doi: 10.1093/sleep/zsz161. [Epub ahead of print]

Dynamic changes in cerebral and peripheral markers of glutamatergic signaling across the human sleep-wake cycle.

Author information

1
Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
2
Sleep & Health Zürich, University Center of Competence, University of Zürich, Zürich Switzerland.
3
Department of Nuclear Medicine, University Hospital Zurich, Zürich, Switzerland.
4
Institute for Regenerative Medicine, University of Zürich, Zürich, Switzerland.
5
Center of MR Research, Children's University Hospital, Zürich, Switzerland.
6
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zürich, Switzerland.

Abstract

Sleep and brain glutamatergic signaling are homeostatically regulated. Recovery sleep following prolonged wakefulness restores efficient functioning of the brain, possibly by keeping glutamatergic signaling in a homeostatic range. Evidence in humans and mice suggested that metabotropic glutamate receptors of subtype-5 (mGluR5) contribute to the brain's coping mechanisms with sleep deprivation. Here, proton magnetic resonance spectroscopy in 31 healthy men was used to quantify the levels of glutamate (Glu), GLX (glutamate-to-glutamine ratio) and GABA (γ-amino-butyric-acid) in basal ganglia (BG) and dorsolateral prefrontal cortex on 3 consecutive days, after ~ 8 (baseline), ~ 32 (sleep deprivation) and ~ 8 hours (recovery sleep) of wakefulness. Simultaneously, mGluR5 availability was quantified with the novel radioligand for positron emission tomography, [18F]PSS232, and the blood levels of the mGluR5-regulated proteins, fragile-X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF) were determined. The data revealed that GLX (p = 0.03) in BG (for Glu: p < 0.06) and the serum concentration of FMRP (p < 0.04) were increased after sleep loss. Other brain metabolites (GABA, N-acetyl-aspartate, choline, glutathione) and serum BDNF levels were not altered by sleep deprivation (pall > 0.6). By contrast, the night without sleep enhanced whole-brain, basal ganglia and parietal cortex mGluR5 availability which was normalized by recovery sleep (pall < 0.05). The findings provide convergent multimodal evidence that glutamatergic signaling is affected by sleep deprivation and recovery sleep. They support a role for mGluR5 and FMRP in sleep-wake regulation and warrant further studies to investigate their causality and relevance for regulating human sleep in health and disease.

KEYWORDS:

BDNF; FMRP; PET-MRS imaging; plasticity; sleep homeostasis

PMID:
31304973
DOI:
10.1093/sleep/zsz161

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