A knock-in mouse model for GABRG2-related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment.

Abstract

De novo mutations in voltage- and ligand-gated ion channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies (DEEs), which often fail to respond to classic antiseizure medications. A de novo mutation (c.C316G > A, p.A106T) in the human GABA type-A receptor γ2 subunit gene (GABRG2) has been recurrently identified in patients with DEE. In this study, we generated a knock-in mouse model replicating the human GABRG2(A106T) variation (Gabrg2^+/A105T in mouse). Gabrg2^+/A105T mice displayed early mortality, spontaneous seizures, and heightened seizure susceptibility. Behavioral analysis revealed phenotypes consistent with DEE, including impaired spatial learning and memory, as well as increased anxiety-like behavior. Reduced γ2 subunit protein expression was detected in the hippocampus of mutant mice, but not other brain regions. Electrophysiological recordings revealed a significant decrease in the amplitude of miniature inhibitory postsynaptic currents (mIPSCs), indicating impaired synaptic GABAergic inhibition. Notably, hippocampal transcriptome profiling provided evidence of neuroinflammation, and histological analysis demonstrated neuronal loss and microglia activation prior to seizure onset. These findings indicate that neuroinflammatory processes, a major theme in acquired epilepsies, may potentially exacerbate epileptogenesis in Gabrg2^+/A105T mice. The knock-in mouse model serves as a potential model for evaluating anti-inflammatory therapies as adjunct treatments for drug-resistant DEEs.