GABA(A) 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 GABRB3 that encodes the GABA(A) receptor (GABA(A)R) β(3) subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate Gabrb3(+/N328D) knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing Gabrb3 (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated Gabrb3(+/N328D) mice for features of LGS. In 2–4-month-old male and female C57BL/J6 wild-type and Gabrb3(+/N328D) mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABA(A)R subunit expression by Western blot. Gabrb3(+/N328D) mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, Gabrb3(+/N328D) mice showed reduced β(3) subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that Gabrb3(+/N328D) mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs.