biostudies-literatureNwosu GININDS NIH HHS8458https://www.ebi.ac.uk/biostudies/studies/S-EPMC10179596biostudies-literatureUnknown24(9)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 <i>GABRB3</i> that encodes the GABA_A receptor (GABA_AR) β₃ subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate <i>Gabrb3</i>^+/N328D knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing <i>Gabrb3</i> (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated <i>Gabrb3</i>^+/N328D mice for features of LGS. In 2-4-month-old male and female C57BL/J6 wild-type and <i>Gabrb3</i>^+/N328D mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABA_AR subunit expression by Western blot. <i>Gabrb3</i>^+/N328D mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, <i>Gabrb3</i>^+/N328D mice showed reduced β₃ subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that <i>Gabrb3</i>^+/N328D mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs.International journal of molecular sciencesGABA_A Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox-Gastaut Syndrome.PMC10179596NS082635NS121718Randhave KZavalin KBiven MLanger KFlamm CPoliquin SShen WKang JQNwosu GIfalseGABA_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 <i>GABRB3</i> that encodes the GABA_A receptor (GABA_AR) β₃ subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate <i>Gabrb3</i>^+/N328D knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing <i>Gabrb3</i> (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated <i>Gabrb3</i>^+/N328D mice for features of LGS. In 2-4-month-old male and female C57BL/J6 wild-type and <i>Gabrb3</i>^+/N328D mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABA_AR subunit expression by Western blot. <i>Gabrb3</i>^+/N328D mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, <i>Gabrb3</i>^+/N328D mice showed reduced β₃ subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that <i>Gabrb3</i>^+/N328D mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs.2023-01-01T00:00:00Z2023 May2025-04-05T09:11:17.209Z2025-04-05T09:11:17.209ZS-EPMC101795963717616510.3390/ijms24098458