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

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