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)

Rapid fast-delta decay following prolonged wakefulness marks a phase of wake-inertia in NREM sleep

“…δ sub-band-specific responses to sleep deprivation in humans. Using previously published data sets [32][33][34][35] , we next assessed whether humans showed a similar δ-power heterogeneity in response to SD. A total of 110 healthy human subjects kept awake for 40 h were included in the analysis.…”

“…To determine whether δ-dynamics were region-specific or represented a global cortical process, a subset of individuals (n = 21) with 19 recording sites were analyzed 35 (Fig. 6c).…”

“…All subjects signed informed consent and were compensated financially for participating. For more details see previous publications [32][33][34][35] . Some subjects were removed across four studies due to EEG signal artifacts, which made time-course analysis of spectral bands difficult.…”

Advances in simultaneous PET/MR for imaging neuroreceptor function

“…This has been exploited by evaluating metabotropic glutamate receptor subtype 5 (mGluR5) availability while measuring glutamate-to-glutamine ratio during recovery of sleep. Interestingly, prolonged wakefulness increased striatal glutamate while also elevating mGluR5 availability, 116 thereby posing a question mark on a common interpretation of linking glutamate release with a reduction in metabotropic receptor availability. Another simultaneous PET/MRI study by Tuura et al 117 demonstrates an acute decrease in striatal glutamate after stimulation with N-acetyl-cysteine was observed with MRS, while no changes in mGluR5 availability were measured by PET.…”

Partial mGlu5 Negative Allosteric Modulator M-5MPEP Demonstrates Antidepressant-Like Effects on Sleep Without Affecting Cognition or Quantitative EEG

“…Functional antagonism of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) represents a promising target with broad therapeutic potential for the treatment of numerous disorders including fragile X syndrome (Yan et al, 2005;Dölen et al, 2007; for review see Nickols and Conn, 2014), Parkinson's disease (Morin et al, 2010), anxiety (Busse et al, 2004;Swanson et al, 2005), depression (Lindemann et al, 2015), acute and neuropathic pain (Montana et al, 2009;Cavallone et al, 2020), and substance use disorder (McGeehan and Olive, 2003;Yararbas et al, 2010;Veeneman et al, 2011;Gould et al, 2015). Moreover, mGlu 5 is involved in homeostatic sleep regulation (Weigend et al, 2019;Aguilar et al, 2020) and modulation of mGlu 5 has potential to normalize sleep disturbances associated with a number of the aforementioned conditions (Lindemann et al, 2015;Gould et al, 2017). For example, in major depressive disorder (MDD), commonly reported sleep disturbances in patients include reductions in rapid eye movement (REM) sleep latency and increased REM duration/density (Armitage, 2007;Steiger and Pawlowski, 2019).…”