GABA Receptors Gone Bad: The Wrong Place at the Wrong Time
Authors: Lagrange Andre 
Published: May 2005

The GABAA-receptor γ2 Subunit R43Q Mutation Linked to Childhood Absence Epilepsy and Febrile Seizures Causes Retention of α1 β2γ2S Receptors in the Endoplasmic Reticulum

Kang J, Macdonald RL

J Neurosci 2004;24:8672–8677

The GABAA-receptor γ2 subunit mutation R43Q is an autosomal dominant mutation associated with childhood absence epilepsy and febrile seizures. Previously, we demonstrated that homozygous α1 β3 γ2L(R43Q)-receptor whole-cell currents had reduced amplitude with unaltered time course, suggesting reduced cell-surface expression of functional receptors. In human embryonic kidney 293-T cells, we demonstrate that both heterozygous and homozygous α1 β2 γ2S(R43Q) GABAA-receptor current amplitudes were reduced when receptors were assembled from coexpressed α1, β2, and γ2S subunits and from β2- α1 tandem subunits coexpressed with the γ2L subunit. By using fluorescence confocal microscopy, we demonstrated that mutant receptors containing enhanced yellow fluorescent protein-tagged γ2S subunits had reduced surface expression and were retained in the endoplasmic reticulum. In addition, by using biotinylation of surface receptors and immunoblotting, we confirmed that α1 β2 γ2S(R43Q)-receptors had reduced surface expression. These results provide evidence that the γ2S(R43Q) mutation impaired GABAA-receptor function by compromising receptor trafficking and reducing surface expression.

Altered Expression of the δ Subunit of the GABAA Receptor in a Mouse Model of Temporal Lobe Epilepsy

Peng Z, Huang CS, Stell BM, Mody I, Houser CR

J Neurosci 2004;24:8629–8639

δ Subunit–containing GABAA receptors are located predominantly at nonsynaptic sites in the dentate gyrus, where they may play important roles in controlling neuronal excitability through tonic inhibition and responses to GABA spillover. Immunohistochemical methods were used to determine whether δ subunit expression was altered after pilocarpine-induced status epilepticus in C57BL/6 mice in ways that could increase excitability of the dentate gyrus. In pilocarpine-treated animals, the normal diffuse labeling of the δ subunit in the dentate molecular layer was decreased by 4 days after status epilepticus (latent period) and remained low throughout the period of chronic seizures. In contrast, diffuse labeling of α4 and γ2 subunits, potentially interrelated GABAA-receptor subunits, was increased during the chronic period. Interestingly, δ subunit labeling of many interneurons progressively increased after pilocarpine treatment. Consistent with the observed changes in δ subunit labeling, physiological studies revealed increased excitability in the dentate gyrus of slices obtained from the pilocarpine-treated mice and demonstrated that physiologic concentrations of the neurosteroid tetrahydrodeoxycorticosterone were less effective in reducing excitability in the pilocarpine-treated animals than in controls. The findings support the idea that alterations in nonsynaptic δ subunit–containing GABAA receptors in both principal cells and interneurons could contribute to increased seizure susceptibility in the hippocampal formation in a temporal lobe epilepsy model.