INVESTIGATING THE RELATIONSHIPS BETWEEN ABSENCE SEIZURES, SLEEP, AND COGNITION IN A RAT MODEL OF <EM >SYNGAP1</EM>-RELATED INTELLECTUAL DISABILITY

SYNGAP1 is a neurodevelopmental disorder (NDD)-associated gene linked with phenotypes including autism, intellectual disability, and absence epilepsy (Hamdan et al., 2009; Mignot et al., 2016; Wright et al., 2022). Sleep disturbances are also highly prevalent in this population (Vlaskamp et al., 2019; Mosini et al., 2025). A heterozygous rat model in which the Syngap C2 and GAP domains are deleted (Syngap^+/Δ-GAP) exhibits several relevant phenotypes, including absence seizure-like spike-wave discharges (SWDs), cognitive deficits including impaired fear extinction (Katsanevaki et al., 2024), and disrupted sleep (Buller-Peralta et al., 2022). Treatment with the anti-seizure drug ethosuximide (ETX) rescues these abnormalities, reducing SWDs, normalizing sleep architecture, and improving fear extinction (unpublished).
Here, we test whether ETX’s effects arise from seizure suppression, improved sleep, or a combination of both. We performed electrographical (EEG) recordings in male and female Syngap^+/+ and Syngap^+/Δ-GAP rats (3-4 months old) to evaluate the effects of ETX, valproic acid, and levetiracetam on SWDs, sleep architecture, and fear extinction. These drugs were selected for their distinct mechanisms of action, to interrogate pathways underlying SWD suppression and their potential influence on sleep-dependent cognitive processes. Additionally, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridine-3-ol, a GABA_A receptor agonist, was administered to experimentally test whether increasing the GABA_A tonic current increase SWDs as in other absence seizure models (Fariello and Golden, 1987; Cope et al., 2009). Given the strong interactions between sleep and epilepsy, and the high prevalence of sleep disturbances in NDDs, understanding the relationships between seizures, cognition, and sleep may inform the development of more targeted therapeutic strategies.