Sleep bidirectionally modulates synaptic strength: opposing dynamics of presynaptic and postsynaptic compartments

RWTH Publications (RWTH Aachen)

Abstract

Sleep plays a crucial role in regulating synaptic plasticity in the brain. The Synaptic Homeostasis Hypothesis (SHY) proposes that synapses are strengthened during wakefulness and selectively downscaled during sleep, resulting in a net reduction in synaptic strength that prevents synaptic saturation and preserves learning capacity. While substantial evidence supports sleep-related synaptic weakening, other studies have reported synaptic enhancement during sleep, leaving synaptic regulation across the sleep-wake cycle controversial. Notably, most previous studies have focused on postsynaptic markers, whereas presynaptic regulation remains poorly understood. In this study, multimodal imaging approaches were employed to systematically investigate synaptic strength in both presynaptic and postsynaptic compartments. Under sleep-wake cycle or sleep deprivation conditions, in vivo longitudinal positron emission tomography (PET) imaging and in vitro autoradiography were used to assess presynaptic function via synaptic vesicle glycoprotein 2A (SV2A). Postsynaptic structure was evaluated by dendritic spine density with Golgi impregnated brain tissue, and it demonstrated that spine density decreased during sleep phase and increased following sleep deprivation, consistent with the SHY. In contrast, presynaptic SV2A density was downscaled following sleep deprivation in both in vivo and in vitro measurements, contrary to SHY predictions. These findings reveal a dissociation between presynaptic and postsynaptic regulation during sleep and wakefulness, highlighting that synaptic compartments may be independently modulated across the sleep-wake cycle. In addition, in vitro evidence on both pre- and post-synaptic side in the somatosensory and visual cortex revealed age-related differences in synaptic organization. Adolescent mice exhibited significantly higher postsynaptic spine density than adult mice at two circadian time points (before sleep and after sleep). Sleep-related synaptic regulation was also age dependent: presynaptic SV2A in adult mice showed greater susceptibility during sleep, while juvenile mice displayed a more pronounced response to sleep deprivation. Further analysis of spines in layers 2/3 and 5 of the neocortical regions illustrated that deeper cortical layers play a more central role in circadian regulation than superficial layers. Furthermore, PET imaging revealed significant sex differences in SV2A-related activity, with male mice exhibiting higher signals than female mice. Adult mice showed stronger PET signals overall, and the inconsistency with in vitro autoradiography suggests that presynaptic functional activity in adult mice may be elevated relative to juvenile mice, rather than reflecting differences in SV2A abundance. However, unlike SV2A autoradiography findings from histological studies in male mice, PET scans did not detect differences in SV2A between young and adult mice following sleep. deprivation. In contrast, adult female mice exhibited a reduced response to sleep deprivation. Together, this study demonstrates that sleep differentially regulates presynaptic and postsynaptic components of synapses in an age-, sex-dependent manner, providing new insights into sleep-dependent synaptic plasticity and neural circuit remodeling during development.

Authors 1

1. Jing Ma corresponding Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen