Abstract
It requires only a bit of self-attention or societal observation to realize that altering natural rhythmic behaviors such as sleep and wake cycles has dramatic effects on health. In reverse, many neuropsychiatric disorders share as a common symptom altered circadian behaviors or altered sleep patterns; and sleep deprivation in healthy individuals is detrimental for memory. However, the molecular mechanisms underlying connections between the circadian cycle, sleep, and brain physiology remain mostly unknown.
This thesis attempts to address these questions by focusing on neuronal synapses, small specialized compartments whose correct composition determines neuronal communication and ultimately brain function. We comprehensively examined these synapses systematically at different times of day characterizing mRNA, protein and phosphorylation rhythms within them. In addition, we challenged normal homeostasis in this scenario by the disruption of sleep wake cycles, to delineate separate functions for sleep and the circadian clock.
The results are presented in two parts, each corresponding to a published manuscript.
In the first manuscript, it is revealed that two-thirds of synaptic transcripts display circadian accumulation independent of the levels in the soma. These mRNAs form two temporal and functional clusters, preceding dawn or dusk. Alongside, the synaptic proteome demonstrates the functional relevance of temporal gating:
RNAs and proteins involving synaptic transmission anticipate the active phase, while those involving translation and energy metabolism anticipate sleep. Unexpectedly, sleep deprivation completely abolishes proteome but not transcript oscillations.
In the second manuscript it is shown that in the synapses half of the phosphoproteins have large-amplitude rhythms peaking as well around dawn and dusk. Kinases follow the same fluctuations and their dynamic phospho-regulation is likely an underlying process. Functionally the phosphoproteome as a whole sustains temporal compartmentalization, favoring synaptic inhibition prior to sleep and excitation before wake. Sleep deprivation abolishes most phosphorylation cycles.
In conclusion, circadian- and sleep-driven mechanisms appear to work hand-inhand to ensure proper physiology by coordinating molecules in space and time. The overall emerging picture is one where in synapses a circadian anticipation of physiological need is achieved by rhythmic messenger RNA accumulation, and this is followed by protein translation and phosphorylation responding directly to sleep-wake cycles.
Noya, Sara B