Hypodopaminergic mice have a sleep phenotype that resembles human Parkinson’s disease

Abstract

Introduction Patients with Parkinson’s Disease (PD) have markedly disturbed sleep. For example, they have difficulty falling and staying asleep, and they commonly experience motor disturbances during both NREM and REM sleep (e.g., RBD). PD patients also suffer from excessive daytime sleepiness and in some cases experience sleep attacks. Although multiple animal models have been used to understand how abnormal dopamine transmission contributes to the cognitive and motor abnormalities in PD, none of them have determined if sleep is impacted in these models. Our current goal was to determine if an established mouse model of PD exhibits a sleep phenotype that resembles PD in human patients. The present study was designed to determine if hypodopaminergic (i.e., reduced brain levels of dopamine) mice have abnormal sleep and waking activity patterns that recapitulate sleep-wake activity in human PD patients. Materials and methods We used both wild-type mice (WT, n = 4) and transgenic mice overexpressing the dopamine transporter (DAT-tg, n = 4). DAT-tg mice experience a 40% reduction in striatal dopamine levels and are an established model of PD. For example, they have significantly reduced brain levels of dopamine similar to that in human PD. DAT-Tg and WT mice were implanted with standard EEG and EMG electrodes for recording wakefulness, NREM and REM sleep. To determine if DAT-tg experience sleep-wake disturbs EEG and EMG activity was recorded for 24 h. Both WT and DAT-tg were habituated to recording instrumentation for 1 day before experimental testing began. results DAT-tg mice exhibit a PD phenotype. They suffer from sleepiness, disturbed sleep patterns and most notably experience sleep attacks. Compared to WT, which never experienced sleep attacks, we found that DAT-tg mice rapidly transitioned directly from active (not quiet) wakefulness into full-blown NREM sleep. Sleep attacks could result from their persistent sleepiness. DAT-tg mice experienced a 110% increase overall levels of NREM sleep compared to WT mice. REM sleep amounts were similar in both groups of mice. DAT-tg mice also suffered from sleep fragmentation. Compared to WT mice, they experienced a 184% increase in the total number of NREM sleep episodes. Conclusion As hypothesized, DAT-tg mice exhibit a PD phenotype. They suffer from persistent sleepiness, have disturbed sleep patterns and experience sleep attacks. These mice are therefore a suitable model for dissecting the mechanisms associated with sleep disturbs in human PD. Acknowledgements The present work was supported by CIHR grant.