Sleep differentially modulates synaptic vesicle protein 2A and spine density across cortical regions and development

Sleep is proposed to regulate synaptic strength; yet, the underlying mechanisms remain debated under the synaptic homeostasis hypothesis (SHY). We examined synaptic vesicle glycoprotein 2A (SV2A) and dendritic spine density in mouse brain across conditions of physiological sleep and sleep deprivation. Spine density decreased during sleep and increased following sleep deprivation, consistent with the SHY. In contrast, [¹⁸F]SynVesT-1 positron emission tomography (PET) imaging and [³H]UCB-J autoradiography revealed reduced SV2A following sleep deprivation. Layer-specific analyses in somatosensory and visual cortices further supported coordinated regulation between SV2A and dendritic spines. Developmentally, adolescent mice exhibited higher baseline SV2A and spine density than adults, with greater SV2A sensitivity to sleep deprivation, whereas adults were more responsive to physiological sleep. Together, these findings reveal bidirectional regulation of pre- and postsynaptic compartments and highlight developmental differences in sleep-dependent synaptic organization.