Effects of Severe Sleep Disruption on the Synaptic Ultrastructure of Young Mice.

There is molecular, electrophysiological and ultrastructural evidence that a net increase in synaptic strength occurs in many brain circuits during spontaneous wake or short sleep deprivation, reflecting ongoing learning. Sleep leads instead to a broad but selective weakening of many forebrain synapses, thus preventing synaptic saturation and decreasing the energy cost of synaptic activity. Whether synaptic potentiation can persist or further increase after long sleep deprivation is unknown. Whether synaptic renormalization can occur during chronic sleep restriction is also unknown. Here we addressed these questions by measuring an established ultrastructural measure of synaptic strength, the axon-spine interface (ASI), in the primary motor cortex of 1) one-month-old adolescent mice chronically sleep restricted (CSR) using a paradigm that decreases NREM and REM sleep by two/thirds; 2) in two-week-old mouse pups sleep deprived for 15 hours, or allowed afterwards to recover for 16 hours. Both groups were compared to mice of the same age that were asleep or awake for a few hours (both sexes). The ASI size of CSR mice (n=3) was comparable to that measured after spontaneous wake or short sleep deprivation and larger than after sleep (n=4/group). In pups, the ASI size increased after short sleep loss (n=3) relative to sleep (n=4), fell below sleep levels after long sleep deprivation (n=4), and remained low after recovery (n=3). Long sleep deprived pups also lost some weight. These results suggest that 1) severe sleep restriction is incompatible with synaptic renormalization; 2) very young mice cannot maintain high synaptic strength during prolonged wake. Statement of Significance The strength of many excitatory synapses increases during wake and decreases during sleep. However, because strong synapses require more energy, synaptic potentiation may be difficult to maintain when wake is enforced well beyond its physiological duration, especially in young animals whose brain is growing. Moreover, because synaptic weakening ultimately requires structural changes and the endocytosis of excitatory receptors, limited and disrupted sleep may not be compatible with synaptic renormalization. We confirmed the first prediction in 2-week-old pups kept awake for 15 hours, and the second prediction in one-month-old mice severely sleep restricted for 4 days.