Mice harboring the T316N variant in the GABA A R γ 2 subunit exhibit sleep-related hypermotor epilepsy phenotypes and hypersynchronization in the thalamocortical pathway.

Objective: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures remains unclear. We previously detected rare variants in GABRG2, which encodes the γ ₂ subunit of γ-aminobutyric acid type A receptor (GABA _A R), in patients with SHE and demonstrated that these variants impaired GABA _A R function in vitro. However, the mechanisms by which GABRG2 variants contribute to seizure attacks during sleep remain unclear.
Methods: In this study, we designed a knock-in (KI) mouse expressing the mouse Gabrg2 T316N variant, corresponding to human GABRG2 T317N variant, using CRISPR/Cas9. Continuous video-electroencephalogram monitoring and in vivo multichannel electrophysiological recordings were performed to explore seizure susceptibility to pentylenetetrazol (PTZ), alterations in the sleep-wake cycle, spontaneous seizure patterns, and synchronized activity in the motor thalamic nuclei (MoTN) and secondary motor cortex (M2). Circadian variations in the expression of total, membrane-bound, and synaptic GABA _A R subunits were also investigated.
Results: No obvious changes in gross morphology were detected in Gabrg2 ^T316N/+ mice compared to their wild-type (Gabrg2 ^+/+ ) littermates. Gabrg2 ^T316N/+ mice share key phenotypes with patients, including sleep fragmentation and spontaneous seizures during sleep. Gabrg2 ^T316N/+ mice showed increased susceptibility to PTZ-induced seizures and higher mortality after seizures. Synchronization of the local field potentials between the MoTN and M2 was abnormally enhanced in Gabrg2 ^T316N/+ mice during light phase, when sleep dominates, accompanied by increased local activities in the MoTN and M2. Interestingly, in Gabrg2 ^+/+ mice, GABA _A R γ2 subunits showed a circadian increase on the neuronal membrane and synaptosomes in the transition from dark phase to light phase, which was absent in Gabrg2 ^T316N/+ mice.
Conclusion: We generated a new SHE mouse model and provided in vivo evidence that rare variants of GABRG2 contribute to seizure attacks during sleep in SHE.
Competing Interests: Declaration of competing interest None.
(Copyright © 2023. Published by Elsevier Inc.)