ALG13 participates in epileptogenesis via regulation of GABA(A) receptors in mouse models

ALG13 (asparagine-linked glycosylation 13) plays crucial roles in the process of N-linked glycosylation. Mutations of the ALG13 gene underlie congenital disorders of glycosylation type I (CDG-I), a rare human genetic disorder with defective glycosylation. Epilepsy is commonly observed in congenital disorders of glycosylation type I (CDG-I). In our study, we found that about 20% of adult ALG13KO knockout mice display spontaneous seizures, which were identified in a simultaneous video and intracranial EEG recording. However, the mechanisms of ALG13 by which deficiency leads to epilepsy are unknown. Whole-cell patch-clamp recordings demonstrated that ALG13KO mice show a marked decrease in gamma-aminobutyric acid A receptor (GABA(A)R)-mediated inhibitory synaptic transmission. Furthermore, treatment with low-dose diazepam (a positive allosteric modulator of GABA(A) receptors), which enhances GABA(A)R function, also markedly ameliorates severity of epileptic seizures in ALG13KO mice. Moreover, ALG13 may influenced the expression of GABA(A)Rα2 membrane and total protein by changing transcription level of GABA(A)Rα2. Furthermore, protein interactions between ALG13 and GABA(A)Rα2 were observed in the cortex of wild-type mice. Overall, these results reveal that ALG13 may be involved in the occurrence of epilepsy through the regulation of GABA(A)R function, and may provide new insight into epilepsy prevention and treatment.