Sleep and diurnal rest-activity rhythm disturbances in a mouse model of Alzheimer’s disease

Abstract

Study Objectives Accumulating evidence suggests a strong association between sleep, amyloid-beta (Aβ) deposition, and Alzheimer’s disease (AD). We sought to determine if (1) deficits in rest-activity rhythms and sleep are significant phenotypes in J20 AD mice, (2) metabotropic glutamate receptor 5 inhibitors (mGluR5) could rescue deficits in rest-activity rhythms and sleep, and (3) Aβ levels are responsive to treatment with mGluR5 inhibitors. Methods Diurnal rest-activity levels were measured by actigraphy and sleep-wake patterns by electroencephalography, while animals were chronically treated with mGluR5 inhibitors. Behavioral tests were performed, and Aβ levels measured in brain lysates. Results J20 mice exhibited a 4.5-h delay in the acrophase of activity levels compared to wild-type littermates and spent less time in rapid eye movement (REM) sleep during the second half of the light period. J20 mice also exhibited decreased non-rapid eye movement (NREM) delta power but increased NREM sigma power. The mGluR5 inhibitor CTEP rescued the REM sleep deficit and improved NREM delta and sigma power but did not correct rest-activity rhythms. No statistically significant differences were observed in Aβ levels, rotarod performance, or the passive avoidance task following chronic mGluR5 inhibitor treatment. Conclusions J20 mice have disruptions in rest-activity rhythms and reduced homeostatic sleep pressure (reduced NREM delta power). NREM delta power was increased following treatment with a mGluR5 inhibitor. Drug bioavailability was poor. Further work is necessary to determine if mGluR5 is a viable target for treating sleep phenotypes in AD.

Sleep/Wake Behavior and EEG Signatures of the TgF344-AD Rat Model at the Prodromal Stage

“…These findings are in line with results from recent studies. In experiments with J20 mice, these animals showed reduced REM sleep if compared to controls [20]. Further, an observed reduction in REM sleep in patients is associated with a higher all-cause dementia risk [21].…”

“…Similar results were described for other rodent models for AD. J20, AβPPswe/PS1∆E9, and APP23 amyloidosis mice also feature lower (relatively) power in the low frequencies and increased (relatively) power in the high frequencies [20,[31][32][33].…”

Metabotropic glutamate receptor 5 regulates synaptic plasticity in a chronic migraine rat model through the PKC/NR2B signal

“…MGluR5, a subtype of type I mGluRs, is a G proteincoupled receptor (GPCR), associated with a variety of nervous system diseases, including pain, Alzheimer's disease [8], and addiction [9]. Previous studies have shown that mGluR5 regulates the induction and maintenance of LTP in the hippocampal CA1 region of rats.…”

Metabotropic Glutamate Receptor 5 Regulates Synaptic Plasticity in a Chronic Migraine Rat Model Through the PKC/NR2B Signal

“…mGluR5, a subtype of type I mGluRs, is a G protein-coupled receptor (GPCR), associated with a variety of nervous system diseases, including pain, Alzheimer's disease [8], and addiction [9]. Previous studies have shown that mGluR5 regulates the induction and maintenance of LTP in the hippocampal CA1 region of rats.…”