Early Disruption of Cortical Sleep-Related Oscillations in a Mouse Model of Dementia With Lewy Bodies (DLB) Expressing Human Mutant (A30P) Alpha-Synuclein

Abstract

Changes in sleep behavior and sleep-related cortical activity have been reported in conditions associated with abnormal alpha-synuclein (α-syn) expression, in particular Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Notably, changes can occur in patients years before the onset of cognitive decline. Sleep-related network oscillations play a key role in memory function, but how abnormal α-syn impacts the generation of such activity is currently unclear. To determine whether early changes in sleep-related network activity could also be observed, prior to any previously reported cognitive dysfunction, we used mice that over-express human mutant α-syn (A30P). Recordings in vivo were performed under urethane anesthesia in the medial prefrontal cortex (mPFC) and CA1 region of the hippocampus in young male (2.5-4 months old) A30P and age-matched wild type (WT) mice. We found that the slow oscillation (SO) < 1 Hz frequency was significantly faster in both the mPFC and hippocampus in A30P mice, and Up-state-associated fast oscillations at beta (20-30 Hz) and gamma (30-80 Hz) frequencies were delayed relative to the onset of the Up-state. Spindle (8-15 Hz) activity in the mPFC was also altered in A30P mice, as spindles were shorter in duration and had reduced density compared to WT. These changes demonstrate that dysregulation of sleep-related oscillations occurs in young A30P mice long before the onset of cognitive dysfunction. Our data suggest that, as seen in patients, changes in sleep-related oscillations are an early consequence of abnormal α-syn aggregation in A30P mice.

Sleep alterations in a mouse model of Spinocerebellar ataxia type 3

“…The copyright holder for this preprint (which this version posted July 5, 2022. ; https://doi.org/10.1101/2022.07.05.498300 doi: bioRxiv preprint during REM and NREM in Q84 mice is reminiscent of increased beta oscillations observed in other neurodegenerative diseases and sleep disorders. Alterations, most frequently increases, in beta oscillations have been observed during wake and sleep states in patients or animal models of PD [60][61][62][63][64][65][66][67][68] , HD 69,70,[79][80][81][82][83][84][71][72][73][74][75][76][77][78] , dementia with Lewy bodies 85,86 , insomnia 60,87 , and RBD 63,[88][89][90] . In PD, beta oscillations in the basal ganglia are usually pathological 60,62,64,67,68,91 and appear to be linked to basal ganglia dysfunction or compensation.…”

Crucial Role of FABP3 in αSyn-Induced Reduction of Septal GABAergic Neurons and Cognitive Decline in Mice

“…Dysfunction of parvalbumin-positive interneurons and gamma oscillations in the hippocampus are also suggested to be related to neuropathology in DLB patients [ 68 ]. Gamma oscillations in the hippocampus and sleep-related ones in the cortex were altered prior to cognitive decline in mice carrying human mutated Snca (A30P) compared to wild-type counterparts [ 69 , 70 , 71 ]. These reports support that disruption of GABAergic in addition to cholinergic neurons in the MS/DB would contribute to impaired neural activity in the hippocampus and cortex, and cognitive impairment in synucleinopathies.…”

Modeling Parkinson's disease‐related symptoms in alpha‐synuclein overexpressing mice

“…Although animal models of RBD were initially created by pontine tegmental lesions, there is evidence of naturally occurring RBD‐like sleep dysfunctions in animals (reviewed in [Schenck & Mahowald, 2002 ]). Sleep disturbances or circadian rhythm dysfunction are included in the validation of multiple models of α‐synucleinopathies (Kudo et al., 2011 ; Shen et al., 2020 ; Stylianou et al., 2020 ).…”

“…Moreover, L61 tg mice show alterations in temporal distribution of sleep, with an increased sleeping time in late day and a decreased time in late night as well as a reduction in neural activity of the SCN (Kudo, Loh, et al., 2011 ). In A30P tg mice, alterations in sleep‐related oscillations were shown in medial prefrontal cortex and hippocampus in 2‐ to 3‐months‐old animals, i.e., several months prior to the occurrence of motor symptoms (Stylianou et al., 2020 ).…”