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

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), glutamate-to-glutamine ratio (GLX), and γ-amino-butyric-acid (GABA) 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, BG, 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. Clinical Trial Registration: www.clinicaltrials.gov (study identifier: NCT03813082).

• Authors: Susanne Weigend, Sebastian C Holst, Valérie Treyer, Ruth L O'Gorman Tuura, Josefine Meier, Simon M Ametamey, Alfred Buck, Hans-Peter Landolt
• Journal: Sleep (Sleep) Vol. 42 Issue 11 (10 21 2019) ISSN: 1550-9109 [Electronic] United States
• PMID: 31304973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].

Chemical References

• Brain-Derived Neurotrophic Factor
• FMR1 protein, human
• Glutamine
• Fragile X Mental Retardation Protein
• Glutamic Acid
• gamma-Aminobutyric Acid

Topics

• Adult
• Basal Ganglia (diagnostic imaging, metabolism)
• Brain (diagnostic imaging, metabolism)
• Brain-Derived Neurotrophic Factor (blood)
• Fragile X Mental Retardation Protein (blood)
• Glutamic Acid (metabolism)
• Glutamine (metabolism)
• Humans
• Male
• Middle Aged
• Positron-Emission Tomography
• Prefrontal Cortex (diagnostic imaging, metabolism)
• Proton Magnetic Resonance Spectroscopy
• Signal Transduction
• Sleep (physiology)
• Sleep Deprivation (diagnostic imaging, metabolism)
• Wakefulness (physiology)
• Young Adult
• gamma-Aminobutyric Acid (metabolism)