11 REM sleep impairment is reverted by absence-seizure treatment in a SYNGAP1 haploinsufficiency rat model of autism and intellectual disability

Sleep is an extremely sensitive biomarker of neurological conditions and is impaired in several neurodevelopmental disorders (NDD). Sleep disturbances are reported in 60% of patients carrying SYNGAP1 gene mutations, an haploinsufficiency associated with intellectual disability (ID), autism spectrum disorder (ASD) and epilepsy. We previously found an absence-seizure phenotype in the novel heterozygous Syngap+/ΔGap rat model, showing spontaneous spike and wave discharges (SWDs) that were blocked by acute treatment with a standard anti-absence drug Ethosuximide (ETX). Here, we assessed sleep impairments in Syngap+/ΔGap rats and tested a possible relation between altered sleep and the seizure phenotype. Wireless EEG+EMG recordings were obtained during 6 consecutive days in 10 Syngap+/ΔGap adults male rats and 10 wildtype littermates. After 2 baseline days, animals were randomly treated with a single i.p injection of either ETX (100 mg/kg, 1ml/kg), or the vehicle during days 3 and 5, respectively. SWDs and sleep states were scored through automated algorithms. Compared to control littermates, Syngap+/ΔGap rats showed increased number of SWDs1 through the whole circadian cycle and a significant decrease of REM sleep across the day2, expressed in shorter bouts. Wake and non-REM sleep displayed less and longer bouts, without total time differences. ETX treatment successfully blocked SWDs in Syngap+/ΔGap rats during the reported drug half-life time, but not during the subsequent dark phase3. Strikingly, REM sleep deficits in Syngap+/ΔGap were reverted during ETX treatment day across the entire circadian cycle4, by increasing the number of REM sleep bouts. No effect was observed on Wake nor non-REM sleep, although the latter showed equivalent number and durations to WT controls during ETX treatment. Our results suggest that seizure activity impairs sleep, possibly by disturbing the normal homeostatic flow of brain states, and ultimately affecting REM sleep expression. (Figure 1)These impairments may contribute to cognitive and social deficits in SYNGAP1 haploinsufficiency.