Absence seizures and sleep-wake abnormalities in a rat model of GRIN2B neurodevelopmental disorder

Pathogenic mutations in GRIN2B are an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism, and intellectual disability. GRIN2B encodes 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 novel Grin2b heterozygous knockout rat model with electroencephalography (EEG) and pharmacological interventions to block spontaneous seizures.

Through western blot analysis we assessed the extent of GluN2B protein knockdown in knockout (Grin2b^+/-) rats compared to controls. We recorded 24-h wireless multi-channel EEG to test whether seizure activity was present and analyzed sleep-wake cycles through a novel automated sleep-scoring algorithm. We tested the effects of systemic and intracerebral reticular thalamic nucleus administration of ethosuximide, a T-type voltage-gated calcium channel blocker, and memantine, a noncompetitive NMDAR antagonist, on seizures.

Compared to wild-type rats, Grin2b^+/- rats had a higher incidence of spontaneous spike and wave discharges (SWDs), the electrographic correlate of absence seizures. SWDs were longer in duration and displayed higher delta band spectral power in Grin2b^+/- animals. Heterozygous animals displayed a reduction in total rapid eye movement sleep and altered distributions of non-rapid eye movement sleep and wake epochs. This was accompanied by a decrease in overall spectral wake power and an increase in beta band power during non-rapid eye movement sleep. The sleep-wake phenotypes were largely uncorrelated with the incidence of SWDs. Systemic ethosuximide reduced the number and duration of SWDs, whereas memantine only reduced their duration. Intrathalamic infusion of both ethosuximide and memantine reduced the number of SWDs.

Our data show that the new rat Grin2b haploinsufficiency model exhibits clinically relevant phenotypes and highlights two potential therapeutic options for GRIN2B-related epilepsy.