Anti-seizure mechanisms of midazolam and valproate at the ?(L51M) variant of the GABAA receptor br

Genetic sequencing is identifying an expanding number of variants of GABAA receptors associated with human epilepsies. We identified a new de novo variant of the 82 subunit (82L51M) of the inhibitory GABAA receptor associated with seizures. Our analysis determined the pathogenicity of the variant and the effects of anti-seizure medications. Our data demonstrates that the variant reduced cell surface trafficking and peak GABA-gated currents. Synaptic currents mediated by variant-containing receptors decayed faster than wild-type and single receptor currents showed that the variant shortened the duration of receptor activity by decreasing receptor open times. We tested the effects of the anti-seizure medications, midazolam, carbamazepine and valproate and found that all three enhance variant receptor surface expression. Additionally, midazolam restored receptor function by increasing single receptor active periods and synaptic current decay times towards wild-type levels. By contrast, valproate increased synaptic peak currents, event frequency and promoted synaptic bursting. Our study identifies a new disease-causing variant to the GABAA receptor, profiles its pathogenic effects and demonstrates how antiseizure drugs correct its functional deficits.

Automated summary

This research identified a new variant of GABAA receptor associated with seizures and studied its pathogenicity and response to anti-seizure drugs. The study found that the variant reduced receptor surface trafficking and peak GABA-gated currents, leading to shorter receptor activity duration. However, certain anti-seizure drugs were able to enhance the variant receptor expression and restore receptor function.