Sleep and synaptic homeostasis: a hypothesis
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.
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.
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