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.

Pharmacological inhibition of S6K1 rescues synaptic deficits and attenuates seizures and depression in chronic epileptic rats

“…As described previously, 26 Golgi staining was performed following the manufacturer's protocols (Hito Golgi‐Cox OptimStain™ Kit). A total of 22–25 dendrites of pyramidal neurons located in the hippocampal CA1 region per group ( N = 4–5) were imaged under bright‐field illumination (T‐PMT) on a Zeiss microscope system (LSM 780) with a 100×/1.4 oil immersion lens and evaluated by FIJI software (Fiji, ImageJ 1.46, NIH).…”

“…As described previously, 26 Golgi staining was performed following the manufacturer's protocols (Hito Golgi-Cox OptimStain™ Kit). A (Figure 1B,D).…”

Research progress on the relationship between Paneth cells-susceptibility genes, intestinal microecology and inflammatory bowel disease

“…If the regulation of the vesicle transport system is abnormal, the normal life activities of cells will be affected[ 106 ]. Abnormal PC vesicle transport, characterized by a reduced number of DCVs containing lysozyme, occurs in CD patients[ 107 ]. A similar phenomenon was also observed in LRRK2 -/- mice.…”