Cerebellar GluN2C protects against sleep deprivation-induced cognitive impairment and motor incoordination

Sleep loss, particularly long-term sleep insufficiency or clinical sleep disorders, is a global health problem that affects millions of people and has been linked to accelerated cognitive decline and increased dementia risk. The cerebellum, traditionally viewed as a motor-control center, is now recognized to modulate emotion, cognition and sleep. Emerging evidence indicates that the cerebellum exhibits sleep stage-dependent activity and is closely associated with learning and memory processes. The N-methyl-D-aspartate (NMDA) receptor subunit GluN2C is highly expressed in cerebellar granule cells, yet its role in sleep-loss-induced cognitive impairment remains unknown. Here, using a 14-day sleep-deprivation (SD) mouse model, we found that SD induced reductions in the mRNA and protein levels of cerebellar GluN2C. Overexpression of Grin2c (the encoding gene of GluN2C) in the cerebellar granule cells restored GluN2C protein to vehicle-group levels and rescued SD-induced cognitive deficits, motor incoordination, and synaptic proteins loss. Additionally, Grin2c overexpression reversed SD-induced decreases in neuronal nitric oxide synthase (nNOS) and nitric oxide (NO). In cultured cerebellar granule cells, a GluN2C agonist increased nNOS and NO, whereas a GluN2C inhibitor decreased both; selective blockade of nNOS abolished the GluN2C-agonist-evoked rise in NO. Our findings identify a previously unrecognized role for GluN2C in cerebellar granule cells in counteracting SD-induced cognitive and motor dysfunction, likely via the nNOS/NO signaling. Targeting GluN2C may therefore offer a therapeutic strategy for sleep-disorder-related cognitive decline and motor incoordination.