Sleep/Wake Regulation and Cortical EEG Are Disturbed in the Neuroligin-3 Rat Model of Autism

SRI Authors: Thomas Kilduff

Abstract

The core features of autism spectrum disorder (ASD) include impaired social communication and restricted/repetitive behaviors. ASD can be further characterized by a range of associated abnormalities, one of which is sleep disruption (e.g., irregular sleep, frequent night awakenings, prolonged awakenings). Therefore, if a proposed animal ASD model is truly translational, some aspects of disrupted sleep would be expected. The present study assessed sleep/wake physiology and quantitative electroencephalography (qEEG) in the neuroligin-3 (Nlgn3) rat model of ASD.Nlgn3 wild type (WT, N=9) and knockout (KO, N=9) male rats were surgically implanted with a telemetry device to record cortical EEG, muscle EMG, core body temperature (CBT) and locomotor activity (LMA). All studies were performed at three months of age. Analyses were based on 24 h recordings. Nlgn3 KO rats spent equivalent times awake compared to WT rats across a 24 h period and CBT was similar between the two genotypes. However, KO rats exhibited greater wake consolidation during the last four hours of the dark phase (rat’s active period), reflected in longer wake bouts and a trend towards fewer wake bouts than WT rats. LMA also significantly increased during this time. KO rats spent less time in NREM sleep across the 24 h period and significantly more time in REM sleep during the light phase (inactive period), resulting in increased REM/NREM ratios during the light phase and the entire 24 h period. EEG spectral power was abnormal during all three behavioral states, particularly in the theta (4-9 Hz) band. KO rats exhibited significant increases in delta (0.5-4 Hz) and theta power during wakefulness, which were most pronounced during the last two hours of the dark phase. Theta power was also elevated during NREM in both light and dark phases. NREM delta was significantly increased during the light phase, while NREM alpha (9-12 Hz) was significantly elevated during the dark phase. Theta during REM sleep also significantly increased across the 24 h period. This study demonstrates the presence of sleep/wake abnormalities in a model of ASD, consistent with the presence of sleep disruptions found in ASD. The observed decreases in NREM and increased wake consolidation are similar to findings of decreased sleep and hyperactivity in ASD individuals. Furthermore, the cortical EEG abnormalities in the Nlgn3 KO rats are analogous to the reported increases in low frequency spectral power during resting-state EEG studies with ASD subjects. These results highlight the utility of preclinical EEG as a translational research tool that can provide valuable insight into the pathogenesis of ASD.

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