GABA Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox-Gastaut Syndrome.

Lennox-Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in that encodes the GABA receptor (GABAR) β subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated mice for features of LGS. In 2-4-month-old male and female C57BL/J6 wild-type and mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABAR subunit expression by Western blot. mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, mice showed reduced β subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs.