Altered GABAA receptor expression in brainstem nuclei and SUDEP in Gabrg2(+/Q390X) mice associated with epileptic encephalopathy.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause for death in individuals with epilepsy. The frequency of SUDEP correlates with the severity of epilepsies and lack of response to antiepileptic drug treatment, but the underlying mechanisms of SUDEP have not been elucidated fully. GABRG2(Q390X) is a mutation associated with the epileptic encephalopathy Dravet syndrome (DS) and with genetic epilepsy with febrile seizures plus (GEFS+) in patients. The Gabrg2(+/Q390X) knockin (KI) mouse phenocopies the major features of DS and GEFS+ and has SUDEP throughout life. The Gabrg2(+/-) knockout (KO) mouse is associated with infrequent absence seizures and represents a model of mild absence epilepsy syndrome without increased mortality. To explore the basis for SUDEP in DS and GEFS+, we compared mutant γ2 subunit and wild-type α1 and β2/3 subunit expression in mice in brainstem nuclei associated with respiratory function including the solitary tract, pre-Botzinger complex and Kolliker-Fuse nuclei. We found that synaptic GABAA receptors were reduced while intracellular nonfunctional γ2(Q390X) subunits were increased in the heterozygous DS and GEFS+ KI mice, but not in the heterozygous absence epilepsy KO mice. Given the critical role of these nuclei in cardiorespiratory function, it is likely the impaired GABAergic transmission and neuronal dysfunction in these brainstem nuclei are involved in the cardiorespiratory collapse in SUDEP. The study provides novel mechanistic insights into cardiorespiratory failure of SUDEP.