Why Does Fever Trigger Febrile Seizures? GABAAReceptor γ2 Subunit Mutations Associated with Idiopathic Generalized Epilepsies Have Temperature-Dependent Trafficking Deficiencies

Abstract

With a worldwide incidence as high as 6.7% of children, febrile seizures are one of the most common reasons for seeking pediatric care, but the mechanisms underlying generation of febrile seizures are poorly understood. Febrile seizures have been suspected to have a genetic basis, and recently, mutations in GABA_A receptor and sodium channel genes have been identified that are associated with febrile seizures and generalized seizures with febrile seizures plus pedigrees. Pentameric GABA_A receptors mediate the majority of fast synaptic inhibition in the brain and are composed of combinations of α(1–6), β(1–3), and γ(1–3) subunits. In αβγ2 GABA_A receptors, the γ2 subunit is critical for receptor trafficking, clustering, and synaptic maintenance, and mutations in the γ2 subunit have been monogenically associated with autosomal dominant transmission of febrile seizures. Here, we report that whereas trafficking of wild-type α1β2γ2 receptors was slightly temperature dependent, trafficking of mutant α1β2γ2 receptors containing γ2 subunit mutations [γ2(R43Q), γ2(K289M), and γ2(Q351X)] associated with febrile seizures was highly temperature dependent. In contrast, trafficking of mutant α1β2γ2 receptors containing an α1 subunit mutation [α1(A322D)] not associated with febrile seizures was not highly temperature dependent. Brief increases in temperature from 37 to 40°C rapidly (A receptors in response to fever.