Fxr1 regulates sleep and synaptic homeostasis

AbstractThe fragile X autosomal homolog 1 (Fxr1) has been GWAS-associated to schizophrenia and insomnia but its contributions to brain functions are unclear. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and engages both global and cell autonomous level processes. We used Crispr/Cas9-mediated somatic knockouts, overexpression, neuronal activity recordings and translatome sequencing, to examine the contribution of Fxr1 to cell-autonomous homeostatic synaptic scaling and global-level sleep homeostasis. Our findings indicate that Fxr1 is downregulated during scaling and sleep deprivation via a Gsk3β dependent mechanism. In both conditions, downregulation of Fxr1 is essential for the homeostatic modulation of synaptic strength. Furthermore, overexpression of Fxr1 during sleep deprivation results in altered EEG signatures and reverts changes of translatome profiles. These findings indicate that Fxr1 represents a shared signaling hub linking cell autonomous homeostatic plasticity and system level sleep homeostasis with potential implications for neuropsychiatric illnesses.

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Fragile X Protein FMRP Is Required for Homeostatic Plasticity and Regulation of Synaptic Strength by Retinoic Acid

Journal of Neuroscience ◽

10.1523/jneurosci.3660-10.2010 ◽

2010 ◽

Vol 30 (50) ◽

pp. 16910-16921 ◽

Cited By ~ 93

Author(s):

M. E. Soden ◽

L. Chen

Keyword(s):

Retinoic Acid ◽

Fragile X ◽

Synaptic Strength ◽

Homeostatic Plasticity ◽

X Protein

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The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling

Science Translational Medicine ◽

10.1126/scitranslmed.aar4338 ◽

2018 ◽

Vol 10 (452) ◽

pp. eaar4338 ◽

Cited By ~ 25

Author(s):

Zhenjie Zhang ◽

Samuele G. Marro ◽

Yingsha Zhang ◽

Kristin L. Arendt ◽

Christopher Patzke ◽

...

Keyword(s):

Mental Retardation ◽

Retinoic Acid ◽

Fragile X ◽

Embryonic Stem ◽

Synaptic Strength ◽

Homeostatic Plasticity ◽

Retinoic Acid Signaling ◽

Ips Cell ◽

Fragile X Mental Retardation ◽

Human Neurons

Fragile X syndrome (FXS) is an X chromosome–linked disease leading to severe intellectual disabilities. FXS is caused by inactivation of the fragile X mental retardation 1 (FMR1) gene, but howFMR1inactivation induces FXS remains unclear. Using human neurons generated from control and FXS patient-derived induced pluripotent stem (iPS) cells or from embryonic stem cells carrying conditionalFMR1mutations, we show here that loss ofFMR1function specifically abolished homeostatic synaptic plasticity without affecting basal synaptic transmission. We demonstrated that, in human neurons, homeostatic plasticity induced by synaptic silencing was mediated by retinoic acid, which regulated both excitatory and inhibitory synaptic strength.FMR1inactivation impaired homeostatic plasticity by blocking retinoic acid–mediated regulation of synaptic strength. Repairing the genetic mutation in theFMR1gene in an FXS patient cell line restored fragile X mental retardation protein (FMRP) expression and fully rescued synaptic retinoic acid signaling. Thus, our study reveals a robust functional impairment caused byFMR1mutations that might contribute to neuronal dysfunction in FXS. In addition, our results suggest that FXS patient iPS cell–derived neurons might be useful for studying the mechanisms mediating functional abnormalities in FXS.

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Time to Be SHY? Some Comments on Sleep and Synaptic Homeostasis

Neural Plasticity ◽

10.1155/2012/415250 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 56

Author(s):

Giulio Tononi ◽

Chiara Cirelli

Keyword(s):

Synaptic Strength ◽

Universal Function ◽

Systematic Bias ◽

Synaptic Homeostasis ◽

The Face ◽

Essential Function ◽

Function Of Sleep ◽

The Brain

Sleep must serve an essential, universal function, one that offsets the risk of being disconnected from the environment. The synaptic homeostasis hypothesis (SHY) is an attempt to identify this essential function. Its core claim is that sleep is needed to reestablish synaptic homeostasis, which is challenged by the remarkable plasticity of the brain. In other words, sleep is “the price we pay for plasticity.” In this issue, M. G. Frank reviewed several aspects of the hypothesis and raised several issues. The comments below provide a brief summary of the motivations underlying SHY and clarify that SHY is a hypothesis not about specific mechanisms, but about a universal, essential function of sleep. This function is the preservation of synaptic homeostasis in the face of a systematic bias toward a net increase in synaptic strength—a challenge that is posed by learning during adult wake, and by massive synaptogenesis during development.

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Sleep after arousal from hibernation is not homeostatically regulated

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.2.r522 ◽

1999 ◽

Vol 276 (2) ◽

pp. R522-R529 ◽

Cited By ~ 10

Author(s):

Jennie E. Larkin ◽

H. Craig Heller

Keyword(s):

Sleep Deprivation ◽

Brain Function ◽

Extended Period ◽

Nrem Sleep ◽

Wave Activity ◽

Ground Squirrels ◽

Recovery Sleep ◽

Sleep Homeostasis ◽

Homeostatic Response ◽

Periodic Arousals

Electroencephalographic slow-wave activity (SWA) in non-rapid eye movement (NREM) sleep is directly related to prior sleep/wake history, with high levels of SWA following extended periods of wake. Therefore, SWA has been thought to reflect the level of accumulated sleep need. The discovery that euthermic intervals between hibernation bouts are spent primarily in sleep and that this sleep is characterized by high and monotonically declining SWA has led to speculation that sleep homeostasis may play a fundamental role in the regulation of the timing of bouts of hibernation and periodic arousals to euthermia. It was proposed that because the SWA profile seen after arousal from hibernation is strikingly similar to what is seen in nonhibernating mammals after extended periods of wakefulness, that hibernating mammals may arouse from hibernation with significant accumulated sleep need. This sleep need may accumulate during hibernation because the low brain temperatures during hibernation may not be compatible with sleep restorative processes. In the present study, golden-mantled ground squirrels were sleep deprived during the first 4 h of interbout euthermia by injection of caffeine (20 mg/kg ip). We predicted that if the SWA peaks after bouts of hibernation reflected a homeostatic response to an accumulated sleep need, sleep deprivation should simply have displaced and possibly augmented the SWA to subsequent recovery sleep. Instead we found that after caffeine-induced sleep deprivation of animals just aroused from hibernation, the anticipated high SWA typical of recovery sleep did not occur. Similar results were found in a study that induced sleep deprivation by gentle handling (19). These findings indicate that the SWA peak immediately after hibernation does not represent homeostatic regulation of NREM sleep, as it normally does after prolonged wakefulness during euthermia, but instead may reflect some other neurological process in the recovery of brain function from an extended period at low temperature.

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The European starling (Sturnus vulgaris) shows signs of NREM sleep homeostasis but has very little REM sleep and no REM sleep homeostasis

SLEEP ◽

10.1093/sleep/zsz311 ◽

2019 ◽

Vol 43 (6) ◽

Cited By ~ 4

Author(s):

Sjoerd J van Hasselt ◽

Maria Rusche ◽

Alexei L Vyssotski ◽

Simon Verhulst ◽

Niels C Rattenborg ◽

...

Keyword(s):

Sleep Deprivation ◽

Eye Movement ◽

Rem Sleep ◽

Spectral Power ◽

Nrem Sleep ◽

Sleep Time ◽

European Starling ◽

Dark Phase ◽

Rapid Eye Movement ◽

Sleep Homeostasis

Abstract Most of our knowledge about the regulation and function of sleep is based on studies in a restricted number of mammalian species, particularly nocturnal rodents. Hence, there is still much to learn from comparative studies in other species. Birds are interesting because they appear to share key aspects of sleep with mammals, including the presence of two different forms of sleep, i.e. non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. We examined sleep architecture and sleep homeostasis in the European starling, using miniature dataloggers for electroencephalogram (EEG) recordings. Under controlled laboratory conditions with a 12:12 h light–dark cycle, the birds displayed a pronounced daily rhythm in sleep and wakefulness with most sleep occurring during the dark phase. Sleep mainly consisted of NREM sleep. In fact, the amount of REM sleep added up to only 1~2% of total sleep time. Animals were subjected to 4 or 8 h sleep deprivation to assess sleep homeostatic responses. Sleep deprivation induced changes in subsequent NREM sleep EEG spectral qualities for several hours, with increased spectral power from 1.17 Hz up to at least 25 Hz. In contrast, power below 1.17 Hz was decreased after sleep deprivation. Sleep deprivation also resulted in a small compensatory increase in NREM sleep time the next day. Changes in EEG spectral power and sleep time were largely similar after 4 and 8 h sleep deprivation. REM sleep was not noticeably compensated after sleep deprivation. In conclusion, starlings display signs of NREM sleep homeostasis but the results do not support the notion of important REM sleep functions.

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Notch Signaling Modulates Sleep Homeostasis and Learning after Sleep Deprivation in Drosophila

Current Biology ◽

10.1016/j.cub.2011.04.001 ◽

2011 ◽

Vol 21 (10) ◽

pp. 835-840 ◽

Cited By ~ 57

Author(s):

Laurent Seugnet ◽

Yasuko Suzuki ◽

Gabriel Merlin ◽

Laura Gottschalk ◽

Stephen P. Duntley ◽

...

Keyword(s):

Sleep Deprivation ◽

Notch Signaling ◽

Sleep Homeostasis

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Pumilio Regulates Sleep Homeostasis in Response to Chronic Sleep Deprivation in Drosophila melanogaster

Frontiers in Neuroscience ◽

10.3389/fnins.2020.00319 ◽

2020 ◽

Vol 14 ◽

Author(s):

Luis A. De Jesús-Olmo ◽

Norma Rodríguez ◽

Marcelo Francia ◽

Jonathan Alemán-Rios ◽

Carlos J. Pacheco-Agosto ◽

...

Keyword(s):

Drosophila Melanogaster ◽

Sleep Deprivation ◽

Sleep Homeostasis ◽

Chronic Sleep Deprivation ◽

Chronic Sleep

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

SLEEP ◽

10.1093/sleep/zsz161 ◽

2019 ◽

Vol 42 (11) ◽

Cited By ~ 4

Author(s):

Susanne Weigend ◽

Sebastian C Holst ◽

Valérie Treyer ◽

Ruth L O’Gorman Tuura ◽

Josefine Meier ◽

...

Keyword(s):

Sleep Deprivation ◽

Metabotropic Glutamate Receptors ◽

Fragile X ◽

Blood Levels ◽

Resonance Spectroscopy ◽

Clinical Trial Registration ◽

Human Sleep ◽

Recovery Sleep ◽

Positron Emission ◽

Glutamatergic Signaling

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)

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