Action potential-dependent α4-containing GABAA receptors contribute to epileptogenicity in focal cortical dysplasia.

FCD is a developmental disorder associated with drug-resistant seizures. Alterations in GABAA receptor-mediated activity contribute to seizures in FCD. However, the exact mechanism of altered GABAergic synaptic activity is still unclear. Previously, we showed increased GABAA receptor α4 subunit expression in FCD. In this study, we investigated whether changes in GABAA receptor configuration at synaptic or extrasynaptic sites contribute to enhanced GABAergic activity in the resected samples of FCD patients. Results showed increase in the frequency and amplitude of spontaneous inhibitory postsynaptic currents on treatment with gaboxadol (agonist for α4δ-containing GABAA receptors). In the presence of tetrodotoxin (voltage-gated Na+ channel inhibitor), frequency and amplitude of miniature inhibitory postsynaptic currents were also increased upon treatment with gaboxadol. However, higher magnitude of change was observed in spontaneous inhibitory postsynaptic currents compared to miniature inhibitory postsynaptic currents on gaboxadol treatment, suggesting action potential-dependent α4-containing GABAA receptor activity may influence epileptogenicity in FCD.