Collapse of feed-forward inhibition underpins hyperexcitability in GABAA receptor gain-of-function epilepsy.

In β3E77K (GABRB3 p.(Glu77Lys)) mice, a use-dependent collapse of feed-forward inhibition linked to enhanced interneuron GABAA signaling drives cortical hyperexcitability.

• Why it matters: Mechanisms connecting GABAA receptor gain-of-function to network hyperexcitability are unclear, limiting how well therapies can be targeted for developmental and epileptic encephalopathies.
• What they did: Engineered β3E77K mice were assessed with seizure phenotyping, electrocorticography, neurological tests, ex vivo CA1 and cortical layer 2/3 recordings, and computational modeling of interneuron-to-pyramidal inhibition.
• The result: β3E77K mice showed spike-wave-like discharges exacerbated by vigabatrin and ameliorated by valproate, with increased GABAA currents and reduced inhibitory currents onto pyramidal neurons, enabling preclinical testing of therapies.

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