Sleep has been hypothesized to rebalance overall synaptic strength after ongoing learning
during waking leads to net synaptic potentiation. If so, because synaptic strength
and size are correlated, synapses on average should be larger after wake and smaller
after sleep. This prediction was recently confirmed in mouse cerebral cortex using
serial block-face electron microscopy (SBEM). However, whether these findings extend
to other brain regions is unknown. Moreover, sleep deprivation by gentle handling
was reported to produce hippocampal spine loss, raising the question of whether synapse
size and number are differentially affected by sleep and waking. Here we applied SBEM
to measure axon–spine interface (ASI), the contact area between pre-synapse and post-synapse,
and synapse density in CA1 stratum radiatum. Adolescent YFP-H mice were studied after
6–8 h of sleep (S = 6), spontaneous wake at night (W = 4) or wake enforced during
the day by novelty exposure (EW = 4; males/females balanced). In each animal ≥425
ASIs were measured and synaptic vesicles were counted in ~100 synapses/mouse. Reconstructed
dendrites included many small, nonperforated synapses and fewer large, perforated
synapses. Relative to S, ASI sizes in perforated synapses shifted toward higher values
after W and more so after EW. ASI sizes in nonperforated synapses grew after EW relative
to S and W, and so did their density. ASI size correlated with presynaptic vesicle
number but the proportion of readily available vesicles decreased after EW, suggesting
presynaptic fatigue. Thus, CA1 synapses undergo changes consistent with sleep-dependent
synaptic renormalization and their number increases after extended wake. SIGNIFICANCE
STATEMENT Sleep benefits learning, memory consolidation, and the integration of new
with old memories, but the underlying mechanisms remain highly debated. One hypothesis
suggests that sleep's cognitive benefits stem from its ability to renormalize total
synaptic strength, after ongoing learning during wake leads to net synaptic potentiation.
Supporting evidence for this hypothesis mainly comes from the cerebral cortex, including
the observation that cortical synapses are larger after wake and smaller after sleep.
Using serial electron microscopy, we find here that sleep/wake synaptic changes consistent
with sleep-dependent synaptic renormalization also occur in the CA1 region. Thus,
the role of sleep in maintaining synaptic homeostasis may extend to the hippocampus,
a key area for learning and synaptic plasticity.