Elsevier

Brain Research Bulletin

Volume 62, Issue 2, 15 December 2003, Pages 143-150
Brain Research Bulletin

Sleep and synaptic homeostasis: a hypothesis

https://doi.org/10.1016/j.brainresbull.2003.09.004Get rights and content

Abstract

During much of sleep, the cerebral cortex is rippled by slow waves, which appear in the electroencephalogram as oscillations between 0.5 and 4.5 Hz. Slow waves are regulated as a function of previous wakefulness, being maximal at the beginning of sleep and then progressively returning to a baseline level. This paper discusses a hypothesis about the significance of slow-wave activity and its homeostatic regulation. The hypothesis is as follows:

  • 1.

    Wakefulness is associated with synaptic potentiation in several cortical circuits;

  • 2.

    Synaptic potentiation is tied to the homeostatic regulation of slow-wave activity;

  • 3.

    Slow-wave activity is associated with synaptic downscaling;

  • 4.

    Synaptic downscaling is tied to the beneficial effects of sleep on performance.

The hypothesized link between sleep and synaptic homeostasis is supported by several lines of evidence and leads to testable predictions.

Introduction

During much of sleep, neurons in the cerebral cortex fire and stop firing together in waves of activity having frequencies of less than 4.5 Hz. Such slow-wave activity, which is the most pronounced electroencephalographic (EEG) feature of non-rapid eye movement (NREM) sleep, is also a reliable predictor of sleep intensity. An important feature of slow-wave activity during sleep is that it increases as a function of previous wakefulness, and it gradually decreases in the course of sleep [6]. This homeostatic regulation suggests that slow-wave activity may be linked to some restorative aspect of sleep. However, the mechanisms and functions of slow-wave homeostasis are still unclear. Here we discuss a hypothesis that links sleep with synaptic homeostasis. The hypothesis is as follows:

  • 1.

    Wakefulness is associated with synaptic potentiation in several cortical circuits;

  • 2.

    Synaptic potentiation is tied to the homeostatic regulation of slow-wave activity;

  • 3.

    Slow-wave activity is associated with synaptic downscaling;

  • 4.

    Synaptic downscaling is tied to the beneficial effects of sleep on performance.

We discuss each of its four points in sequence.

Section snippets

Wakefulness and synaptic potentiation

During wakefulness, when animals explore novel situations, attend to their surroundings, react to sensory stimuli, perform motor tasks, think, make associations, and are punished or rewarded, they learn about their environment. Underlying learning are long-lasting changes in the strength or number of synaptic connections between neurons, which are mediated by complicated cascades of cellular events. Among the best documented molecular correlates of learning are the phosphorylation of

Synaptic potentiation and slow-wave homeostasis

One of the best established facts in sleep regulation in mammals is that slow-wave activity increases in proportion to the duration of prior wakefulness and progressively decreases during sleep [5]. The present hypothesis states that the homeostatic regulation of slow-wave activity is tied to the amount of synaptic potentiation that has occured during previous wakefulness. Specifically, the higher the amount of synaptic potentiation in cortical circuits during wakefulness, the higher the

Slow-wave homeostasis and synaptic downscaling

We have assumed that LTP-related changes occuring in the cortex during wakefulness lead to a net increase in synaptic weight onto neurons, and that such increase is reflected in an increased slow-wave activity. Is such slow-wave activity a mere epiphenomenon, or does it have some functional significance? According to the hypothesis, slow waves occuring in the cortex during sleep would actively promote a generalized depression or downscaling of synapses. In this way, the total synaptic weight to

Synaptic downscaling and performance

The last part of the hypothesis states that active synaptic downscaling occurring during sleep is beneficial for cellular functions and is tied to overnight performance improvement. Undoubtedly, many aspects of behavioral performance improve after sleep and are negatively impacted by sleep deprivation, and it is conceivable that avoiding synaptic overload by maintaining synaptic homeostasis would be beneficial for many cellular processes, such as energy metabolism and membrane maintenance. Here

Caveats and conclusions

Clearly, many aspects of the hypothesis presented here are bound to be inaccurate, incomplete, or outright wrong. Inaccuracy is guaranteed by the complexity of biological systems. Thus, the suggestion that the key mechanism of downscaling is the internalization of AMPA receptors during the up–down transition of the slow oscillation is undoubtedly simplistic. As an example of incompleteness, the hypothesis assumes that slow-wave activity is locally regulated in the cortex, but it does not

Acknowledgements

We thank M.F. Ghilardi, S. Hill, R. Huber, M. Massimini, and N. Rattenborg. This work was supported by grant no. RO1-MH65135.

References (56)

  • A.Y. Klintsova et al.

    Synaptic plasticity in cortical systems

    Curr. Opin. Neurobiol.

    (1999)
  • G.W. Knott et al.

    Formation of dendritic spines with GABAergic synapses induced by whisker stimulation in adult mice

    Neuron

    (2002)
  • H.Y. Man et al.

    Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization

    Neuron

    (2000)
  • P. Meerlo et al.

    A social conflict increases EEG slow-wave activity during subsequent sleep

    Physiol. Behav.

    (2001)
  • M. Sheng et al.

    AMPA receptor trafficking and synaptic plasticity: major unanswered questions

    Neurosci. Res.

    (2003)
  • P.J. Sjostrom et al.

    Rate, timing, and cooperativity jointly determine cortical synaptic plasticity

    Neuron

    (2001)
  • G.G. Turrigiano

    Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same

    Trends Neurosci.

    (1999)
  • G.G. Turrigiano

    AMPA receptors unbound: membrane cycling and synaptic plasticity

    Neuron

    (2000)
  • G.G. Turrigiano et al.

    Hebb and homeostasis in neuronal plasticity

    Curr. Opin. Neurobiol.

    (2000)
  • M.P. Walker et al.

    Practice with sleep makes perfect: sleep-dependent motor skill learning

    Neuron

    (2002)
  • C.S. Wallace et al.

    Correspondence between sites of NGFI-A induction and sites of morphological plasticity following exposure to environmental complexity

    Brain Res. Mol. Brain Res.

    (1995)
  • F. Amzica et al.

    Disconnection of intracortical synaptic linkages disrupts synchronization of a slow oscillation

    J. Neurosci.

    (1995)
  • G. Aston-Jones et al.

    Activity of norepinephrine-containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle

    J. Neurosci.

    (1981)
  • M. Bazhenov et al.

    Model of thalamocortical slow-wave sleep oscillations and transitions to activated states

    J. Neurosci.

    (2002)
  • A.A. Borbely

    From slow waves to sleep homeostasis: new perspectives

    Arch. Ital. Biol.

    (2001)
  • A.A. Borbely, P. Achermann, Sleep homeostasis and models of sleep regulation, in: M.H. Kryger, T. Roth, W.C. Dement...
  • C. Cajochen et al.

    Power density in theta/alpha frequencies of the waking EEG progressively increases during sustained wakefulness

    Sleep

    (1995)
  • C. Cajochen et al.

    Frontal predominance of a relative increase in sleep delta and theta EEG activity after sleep loss in humans

    Sleep Res. Online

    (1999)
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