0276 SLEEP ENHANCEMENT ASSOCIATED WITH REDUCED ALPHA-SYNUCLEIN ACCUMULATION IN THE BRAIN CORTEX OF VESICULAR MONOAMINE TRANSPORTER 2 DEFICIENT MICE SUFFERING FROM INCREASED AROUSAL

Abstract Introduction: Parkinson’s disease (PD) is the second most common neurodegenerative disease in the general population. The hallmark of the disease is a staggering loss of dopaminergic neurons in substantia nigra pars compacta and intracellular deposits of aggregated α-synuclein. The disease manifests with motor and non-motor symptoms, including bradykinesia, tremor, rigidity and sleep-wake disturbances (SWD). SWDs are one of the most frequent non-motor symptoms of PD, often preceding the onset of other symptoms and, despite growing interest in studying SWD in the context of PD, there is a lack of appropriate murine models. Some lines of evidence recently suggested that sleep deficits correlate with increased burden in neurodegenerative disease and that sleep might alleviate disease severity by increasing clearance of metabolites and proteins from interstitial space, which could prove beneficial in diseases with protein accumulation/aggregation as primary pathology. Methods: We performed EEG/EMG recordings in vesicular monoamine transporter 2 (VMAT2) deficient mice at age of 5 months. Afterwards, at age of 14 months we investigated whether sleep modulation by means of pharmacological sleep induction and chronic REM sleep restriction had an effect on alpha-synuclein accumulation in the brain of VMAT2 deficient mice and behavioral symptoms. Results: EEG/EMG recordings in VMAT2 deficient mice (n=6) and wild type (WT) littermates (n=7) at age of 5 months shows that VMAT2 deficient animals present SWD and EEG changes similar to those seen in PD, namely: increased arousal, decreased time spent in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep and lower sleep efficiency. Furthermore, our results suggest that alpha-synuclein burden was reduced in the sleep-induced (SI) group as compared to the untreated (Ctrl) group. However, we found sleep modulation not associated with improved motor ability, which probably indicates hypodopaminergia as the primary cause of the phenotype as opposed to synucleopathy. Conclusion: Overall, our results suggest that VMAT2 deficient mice present increased arousal and reduced sleep efficiency and that reversing such sleep traits by pharmacological sleep enhancement may have an alleviating effect on the alpha-synuclein pathology present in this murine PD model. Support (If Any): none.