LRRK2 Deficiency Aggravates Sleep Deprivation-Induced Cognitive Loss by Perturbing Synaptic Pruning in Mice

Abstract

Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are associated with pronounced sleep disorders or cognitive dysfunction in neurodegenerative diseases. However, the effects of LRRK2 deficiency on sleep rhythms and sleep deprivation-related cognitive changes, and the relevant underlying mechanism, remain unrevealed. In this study, Lrrk2-/- and Lrrk2+/+ mice were subjected to normal sleep (S) or sleep deprivation (SD). Sleep recording, behavioral testing, Golgi-cox staining, immunofluorescence, and real-time PCR were employed to evaluate the impacts of LRRK2 deficiency on sleep behaviors and to investigate the underlying mechanisms. The results showed that after SD, LRRK2-deficient mice displayed lengthened NREM and shortened REM, and reported decreased dendritic spines, increased microglial activation, and synaptic endocytosis in the prefrontal cortex. Meanwhile, after SD, LRRK2 deficiency aggravated cognitive impairments, especially in the recall memory cued by fear conditioning test. Our findings evidence that LRRK2 modulates REM/NREM sleep and its deficiency may exacerbate sleep deprivation-related cognitive disorders by perturbing synaptic plasticity and microglial synaptic pruning in mice.