Differential inflammation responses determine the variable phenotypes of epilepsy induced by GABRG2 mutations

Objective: To explore the mechanism involved in variable phenotypes of epilepsy models induced by gamma-aminobutyric acid type A gamma 2 subunit (GABRG2) mutations. Methods: The zebrafish carrying wild-type (WT) GABRG2, mutant GABRG2(P282S), GABRG2(F343L) and GABRG2(I107T) were established by Tol2kit transgenesis system and Gateway method. Behavioral analysis of different transgenic zebrafish was performed with the DanioVision Video-Track framework and the brain activity was analyzed by field potential recording with MD3000 Bio-signal Acquisition and Processing System. The transcriptome analysis was applied to detect the underlying mechanisms of variable phenotypes caused by different GABRG2 mutations. Results: The established Tg(hGABRG2(P282S)) zebrafish showed hyperactivity and spontaneous seizures, which were more sensitive to chemical and physical epileptic stimulations. Traditional antiepileptic drugs, such as Clonazepam (CBZ) and valproic acid (VPA), could ameliorate the hyperactivity in Tg(hGABRG2(P282S)) zebrafish. The metabolic pathway was significantly changed in the brain transcriptome of Tg(hGABRG2(P282S)) zebrafish. In addition, the behavioral activity, production of pro-inflammatory factors, and activation of the IL-2 receptor signal pathway varied among the three mutant zebrafish lines. Conclusion: We successfully established transgenic zebrafish epileptic models expressing human mutant GABRG2(P282S), in which CBZ and VPA showed antiepileptic effects. Differential inflammatory responses, especially the SOCS/JAK/STAT signaling pathway, might be related to the phenotypes of genetic epilepsy induced by GABRG2 mutations. Further study will expand the pathological mechanisms of genetic epilepsies and provide a theoretical basis for searching for effective drug treatment.