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.
Highlights
Dementia with Lewy bodies (DLB) is the second most common cause of dementia after Alzheimer’s disease (AD) (Walker et al, 2015)
There was a trend for the slow oscillation (SO) to be smaller in all subregions of the medial prefrontal cortex (mPFC) in A30P mice there was no statistical difference in the amplitude of the SO (Figure 2C)
We found that the Up-state was significantly shorter (Figure 2E) in the PrL and dorsal peduncular region (DP) regions [F(1,19) = 5.93, p < 0.05], while the Down-state was significantly shorter in all mPFC regions [F(1,19) = 9.63, p < 0.01] in A30P mice (Figure 2F)
Summary
Dementia with Lewy bodies (DLB) is the second most common cause of dementia after Alzheimer’s disease (AD) (Walker et al, 2015). DLB is characterized by dementia, cognitive fluctuations, rapid eye movement (REM) sleep behavioral disorder (RBD), parkinsonism and visual hallucinations (McKeith et al, 2017). NREM sleep is characterized by a SO < 1 Hz and sleep spindles at 8 – 15 Hz (Volgushev et al, 2006; Ruiz-Mejias et al, 2011). Both REM and NREM sleep play a central role in memory consolidation and synaptic plasticity (Timofeev and Chauvette, 2017; Klinzing et al, 2019; Puentes-Mestril et al, 2019)
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