TY - JOUR T1 - Why Does Fever Trigger Febrile Seizures? GABA<sub>A</sub> Receptor γ2 Subunit Mutations Associated with Idiopathic Generalized Epilepsies Have Temperature-Dependent Trafficking Deficiencies JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2590 LP - 2597 DO - 10.1523/JNEUROSCI.4243-05.2006 VL - 26 IS - 9 AU - Jing-Qiong Kang AU - Wangzhen Shen AU - Robert L. Macdonald Y1 - 2006/03/01 UR - http://www.jneurosci.org/content/26/9/2590.abstract N2 - 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 GABAA receptor and sodium channel genes have been identified that are associated with febrile seizures and generalized seizures with febrile seizures plus pedigrees. Pentameric GABAA 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 GABAA 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 (&lt;10 min) impaired trafficking and/or accelerated endocytosis of heterozygous mutant α1β2γ2 receptors containing γ2 subunit mutations associated with febrile seizures but not of wild-type α1β2γ2 receptors or heterozygous mutant α1(A322D)β2γ2 receptors, suggesting that febrile seizures may be produced by a temperature-induced dynamic reduction of susceptible mutant surface GABAA receptors in response to fever. ER -