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The Journal of Neuroscience, March 1, 2006, 26(9):2590-2597; doi:10.1523/JNEUROSCI.4243-05.2006

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Neurobiology of Disease
Why Does Fever Trigger Febrile Seizures? GABA_A Receptor 2 Subunit Mutations Associated with Idiopathic Generalized Epilepsies Have Temperature-Dependent Trafficking Deficiencies

Jing-Qiong Kang,¹ Wangzhen Shen,¹ and Robert L. Macdonald^1,2,3

¹Departments of Neurology, ²Molecular Physiology and Biophysics, and ³Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37212

Correspondence should be addressed to Dr. Robert L. Macdonald, Vanderbilt University Medical Center, 6140 Medical Research Building III, 465 21st Avenue, South, Nashville, TN 37232-8552. Email: robert.macdonald{at}vanderbilt.edu

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 (1–6), (1–3), and (1–3) subunits. In 2 GABA_A receptors, the 2 subunit is critical for receptor trafficking, clustering, and synaptic maintenance, and mutations in the 2 subunit have been monogenically associated with autosomal dominant transmission of febrile seizures. Here, we report that whereas trafficking of wild-type 122 receptors was slightly temperature dependent, trafficking of mutant 122 receptors containing 2 subunit mutations [2(R43Q), 2(K289M), and 2(Q351X)] associated with febrile seizures was highly temperature dependent. In contrast, trafficking of mutant 122 receptors containing an 1 subunit mutation [1(A322D)] not associated with febrile seizures was not highly temperature dependent. Brief increases in temperature from 37 to 40°C rapidly (<10 min) impaired trafficking and/or accelerated endocytosis of heterozygous mutant 122 receptors containing 2 subunit mutations associated with febrile seizures but not of wild-type 122 receptors or heterozygous mutant 1(A322D)22 receptors, suggesting that febrile seizures may be produced by a temperature-induced dynamic reduction of susceptible mutant surface GABA_A receptors in response to fever.

Key words: GABA_A receptors; temperature; febrile seizures; 2 subunit; trafficking; 2(Q351X); 2(R43Q); 2(K289M); 1(A322D)

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Received Oct. 5, 2005; revised Jan. 19, 2006; accepted Jan. 22, 2006.

Correspondence should be addressed to Dr. Robert L. Macdonald, Vanderbilt University Medical Center, 6140 Medical Research Building III, 465 21st Avenue, South, Nashville, TN 37232-8552. Email: robert.macdonald{at}vanderbilt.edu

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