Absence seizures and sleep abnormalities in a rat model ofGRIN2Bneurodevelopmental disorder

Abstract

Pathogenic mutations inGRIN2Bare an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism and intellectual disability.GRIN2Bencodes the GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs), which are ionotropic glutamate receptors critical for normal development of the nervous system and synaptic plasticity. Here, we characterized a novelGRIN2Bheterozygous knockout rat model with 24-hour EEG recordings. We found rats heterozygous for the deletion (Grin2b+/-) had a higher incidence of spontaneous absence seizures than wild-type rats (Grin2b+/+). Spike and wave discharges, the electrographic correlate of absences seizures, were longer in duration and displayed increased higher overall spectral power inGrin2b+/-animals than those inGrin2b+/+. Heterozygous mutant rats also had abnormal sleep-wake brain state dynamics over the circadian cycle. Specifically, we identified a reduction in total rapid eye movement sleep and, altered distributions of non-rapid eye movement sleep and wake epochs, when compared to controls. This was accompanied by an increase in overall spectral power during non-rapid eye movement sleep inGrin2b+/-. The sleep-wake phenotypes were largely uncorrelated to the incidence of spike and wave discharges. We then tested the antiseizure efficacy of ethosuximide, a T-type voltage-gated calcium channel blocker used in the treatment of absence seizures, and memantine, a noncompetitive NMDAR antagonist currently explored as a mono or adjunctive treatment option in NMDAR related neurodevelopmental disorders. Ethosuximide reduced the number and duration of spike and wave discharges, while memantine did not affect the number of spike and wave discharges but reduced their duration. These results highlight two potential therapeutic options forGRIN2Brelated epilepsy. Our data shows the new ratGRIN2Bhaploinsufficiency model exhibits clinically relevant phenotypes. As such, it could prove crucial in deciphering underlying pathological mechanisms and developing new therapeutically translatable strategies forGRIN2Bneurodevelopmental disorders.