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The Journal of Neuroscience, March 1, 2006, 26(9):2590-2597; doi:10.1523/JNEUROSCI.4243-05.2006
 Previous Article
Neurobiology of Disease
Why Does Fever Trigger Febrile Seizures? GABAA Receptor  2 Subunit Mutations Associated with Idiopathic Generalized Epilepsies Have Temperature-Dependent Trafficking Deficiencies
Jing-Qiong Kang,1
Wangzhen Shen,1 and
Robert L. Macdonald1,2,3
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 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  (1–6),  (1–3), and  (1–3) subunits. In 2 GABAA 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 GABAA receptors in response to fever.
Key words: GABAA receptors; temperature; febrile seizures; 2 subunit; trafficking; 2(Q351X); 2(R43Q); 2(K289M); 1(A322D)
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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