DISTINCT SPECTRAL, CONNECTIVITY, AND FIRING DYNAMICS AROUND SEIZURES IN RAT MODELS OF SYNGAP1 AND GRIN2B NEURODEVELOPMENTAL DISORDERS

Neurodevelopmental disorders, including autism and intellectual disability, are highly comorbid with epilepsy, reported with hundreds of associated mutations. Two knockout models of common monogenic neurodevelopmental disorders, SYNGAP1 and GRIN2B, display spontaneous absence seizures. We hypothesise that each mutation differentially affects circuit mechanisms and contributes to seizures.
Using SYNGAP1 rats in which the GAP-C2 domains of the SYNGAP1 gene had been knocked out (SYNGAP^+/Δ−GAP), and heterozygous knockouts of the GRIN2B gene (GRIN2B^+/-), we performed 24-hour 16-channel grid EEG recordings and identified spike-wave-discharges (SWDs), the electrophysiological correlate of a sudden behavioural arrest prevalent in mutant animals. We compared absence seizure number, duration, spectral power, and connectivity through imaginary coherence across the models. To further examine firing dynamics, we utilised 64-channel silicon probes to record single-unit activity around SWDs in the somatosensory cortex and thalamus.
While SYNGAP^+/Δ−GAP and GRIN2B^+/- do not differ in the number of seizures, SYNGAP^+/Δ−GAP displayed longer seizure episodes than GRIN2B^+/-. Spectral analyses reveal a gradual decrease in higher-frequency power before seizures only in SYNGAP1, while GRIN2B display much quicker recovery of spectral power after seizure termination. Functional connectivity analysis revealed differences in intrahemispheric and bihemispheric connectivity during SWDs. Single-unit analysis in relation to network activity and seizures is ongoing.
Our study yields novel insights into how mutations in SYNGAP1 and GRIN2B generate SWDs, and results in unique properties of absence seizures in each model, thereby revealing new cellular and network targets to prevent seizures and other comorbidities.