NREM SLEEP OSCILLATIONS SHAPE SYNAPTIC PROTEOME DYNAMICS TO SUPPORT SYNAPTIC STABILIZATION

Sleep plays an important role in cognition, particularly in memory consolidation, and sleep disturbances are highly prevalent across neurodevelopmental disorders (NDDs) such as SYNGAP1-Related Disorders (SYNGAP1-RD). Increasing evidence indicates that sleep remodels the synaptic proteome to regulate synaptic function; however, the mechanisms driving this remodelling and its functional consequences remain poorly understood. Here, we combine 24-hour EEG recordings with time-resolved synaptic proteomics in a model of SYNGAP1-RD to uncover a mechanism linking slow-waves and spindles, two major NREM sleep oscillations, to changes in the proteomic composition of synapses. Our results show that remodelling of the synaptic proteome during the rest period is associated with molecular signatures consistent with synaptic stabilization. Importantly, sleep deprivation selectively downregulates key stabilization-associated synaptic proteins, suggesting that sleep promotes this proteomic state. Furthermore, the increase in slow waves and decrease in spindles found in Syngap1^+/- mice coincide with a marked dysregulation of synaptic proteome remodeling and synaptic function organization, especially during the rest period. In line with the proposed roles of slow waves and spindles in synaptic downscaling and potentiation, respectively, their unbalance biased the synaptic proteome toward synaptic weakening rather than stabilization. Together, our findings identify a putative pathological mechanism whereby disrupted brain oscillations lead to aberrant synaptic proteome dynamics. This could have important cognitive implications for NDDs and other neurological conditions with aberrant brain oscillations.