Authors :
Presenting Author: Nour Omar, PhD Candidate – Stanford University
Kala Nair, PhD – Stanford University
Azin E Amini, PhD – Stanford University
Maria-Belen Perez-Ramirez, PhD – Stanford University
Cordelia Smidth, MD Student – Stanford University
Rubi Quinto, Undergraduate – Stanford University
John Hegarty, PhD – Stanford University
Juliet Knowles, MD/PhD – Stanford University
Rationale:
Haploinsufficiency of the post-synaptic protein SYNaptic GTPase Activating Protein 1 (SynGAP1), resulting from pathogenic variants in the SynGAP1 gene, leads to a developmental and epileptic encephalopathy (DEE) characterized by a high prevalence of epilepsy and autism spectrum disorder (ASD). Generalized epilepsy, typically beginning in early childhood (age 2-3 years old), follows a progressive course with worsening seizures over time, and is found in 98% of affected individuals, including absence and other seizure types. An ASD diagnosis is made in 50-80% of individuals with SYNGAP1-DEE. Clinical data suggest that developmental delay and ASD often emerge concurrently with or after seizure onset, but whether there is a causal link underlying the correlation between epilepsy and ASD in SynGAP1-related DEE has not been extensively explored. We investigated the relationship between absence seizures and models of core social behaviors of ASD in SynGAP1+/- mice.
Methods:
SynGAP1+/- mice and wildtype (SynGAP1+/+; WT) littermate controls were randomized to either vehicle or ETX, administered at 400 mg/kg/day ad libitum, via drinking water, starting at post-natal day (P)90. All mice underwent 24-hour video EEG recordings at P65, P90 and P120. and testing in the 3-chamber social interaction test at P60 and P115.
Results:
We observed progressively increasing generalized absence seizures in Syngap1+/- mice; frequency increased from 8+/-1 seizures per hour at P65 to 25+/-4 seizures per hour at P120 (P=0.0001), indicative of epilepsy progression. At P60, before epilepsy progression, SynGAP1+/- mice did not differ from WT littermates in social interaction, based on performance in the 3-chamber social interaction test (measured with social interaction index, SII). However, at P115, following epilepsy progression, SynGAP1+/- mice exhibited a reduction in social behaviors, reflected by reduced SII compared to age-matched WT controls. Seizure burden in SynGAP1+/- mice with established epilepsy was correlated with SII (R2= 0.96, P=0.0006). To test the relationship between seizures and ASD-associated social behaviors, ETX was administered for one month beginning at P90, before epilepsy progression. After one month of treatment (P120), ETX significantly reduced the number of seizures to seizures in SynGAP1+/- mice when compared to the vehicle-treated group (P=0.0013). Whereas vehicle-treated SynGAP1+/- mice showed reduced social behaviors (low SII scores), ETX treated SynGAP1+/- mice exhibited preserved sociability, with SII values comparable to both WT-vehicle and WT-ETX groups.
Conclusions:
These findings demonstrate that epilepsy progression in mice with SynGAP1 haploinsufficiency is correlated with the emergence of ASD-like social behaviors. Pharmacological suppression of seizures ameliorates these deficits, suggesting a pivotal role for seizures in the emergence of ASD. These results suggest that seizure-induced, maladaptive plasticity contributes to neurodevelopmental conditions in people with SynGAP1-DEE, and point to the need for further mechanistic study.
Funding:
SynGAP1 Research Fund, Stanford Maternal and Children’s Health Research Institute