Sleep Spindles and Fragmented Sleep as Prodromal Markers in a Preclinical Model of LRRK2-G2019S Parkinson's Disease

Abstract

Sleep disturbances co-occur with and precede the onset of motor symptoms in Parkinson's disease (PD). We evaluated sleep fragmentation and thalamocortical sleep spindles in mice expressing the p.G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene, one of the most common genetic forms of PD. Thalamocortical sleep spindles are oscillatory events that occur during slow-wave sleep that are involved in memory consolidation. We acquired data from electrocorticography, sleep behavioral measures, and a rotarod-based motor enrichment task in 28 LRRK2-G2019S knock-in mice and 27 wild-type controls (8-10 month-old males). Sleep was more fragmented in LRRK2-G2019S mice; sleep bouts were shorter and more numerous, even though total sleep time was similar to controls. LRRK2-G2019S animals expressed more sleep spindles, and individual spindles were longer in duration than in controls. We then chronically administered the LRRK2-inhibitor MLi-2 in-diet to n = 12 LRRK2-G2019S and n = 15 wild-type mice for a within-subject analysis of the effects of kinase inhibition on sleep behavior and physiology. Treatment with MLi-2 did not impact these measures. The data indicate that the LRRK2-G2019S mutation could lead to reduced sleep quality and altered sleep spindle physiology. This suggests that sleep spindles in LRRK2-G2019S animals could serve as biomarkers for underlying alterations in sleep networks resulting from the LRRK2-G2019S mutation, and further evaluation in human LRRK2-G2019S carriers is therefore warranted.

Sleep and circadian rhythms in Parkinson’s disease and preclinical models

“…Further, in LRRK2 -PD, EDS and RBD are typically absent from the pre-symptomatic stages of the disease [ 184 , 266 ]. The sleep fragmentation observed in the preclinical murine LRRK2-G2019S model represents one of the four sleep complaints experienced by 56% of LRRK2-PD patients [ 184 , 267 ]. It remains to be shown whether the sleep fragmentation in these mice is specific for NREM or REM sleep as the study did not differentiate between sleep stages.…”

Modeling Parkinson’s disease in LRRK2 rodents

“…Studies in G2019S KI mice compared with WT controls ( Table 4 ) revealed no changes in spontaneous locomotion in motility cages at 5 months [ 62 ] or rotarod performance at 2 months [ 74 ]. On the other hand, G2019S KI mice outperformed WT controls in the OF and rotarod test at 6 months [ 63 , 81 , 70 ], a finding that, however, was not confirmed by more recent studies [ 64 , 71 ]. R1441C/G KI mice do not show differences in spontaneous locomotion or rotarod performance compared with WT counterparts up to 22 months [ 65 , 66 , 74 ].…”

“…Careful sleep analysis was carried out in 8–10-month-old G2019S KI mice [ 71 ] ( Table 4 ). These mice slept a similar amount of time as WT counterparts, but the number of sleep bouts was greater and their duration shorter, indicating sleep fragmentation.…”

“…Moreover, an increase in spindle density and duration was observed in G2019S KI mice. These events, however, were not reversed by in-diet administration of MLi-2 at an equivalent dose of 60 mg/kg, suggesting LRRK2 kinase hyperactivity was not involved [ 71 ]. An increase of time spent in REM sleep was observed in BAC hG2019S mice compared with non-transgenic controls at the age of 12 and 18 months, which was associated with an increase in the levels of the circadian locomotor output cycles protein kaput (CLOCK) protein in the midbrain [ 86 ].…”

Animal models of Parkinson’s disease: a guide to selecting the optimal model for your research

“…Of the transgenic models, BAC-SNCA A53T mice display REM sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age [ 67 ]. LRRK2 G2019S mice also display sleep problems, manifest as increased sleep fragmentation that reduces sleep quality [ 190 ]. However, despite the clear link between GBA mutations and REM sleep behaviour disorder in patients [ 191 ], there are no reports to our knowledge of altered sleep patterns in GBA mice.…”