Increased levels of α4-containing GABA receptors in focal cortical dysplasia: A possible cause of benzodiazepine resistance.

Benzodiazepines are the first choice of anti-epileptic drugs used to treat seizures. However, it has been seen that their efficacy decreases with time leading to drug insensitivity, plausibly caused by an alteration in the expression of the benzodiazepine biding site on GABA receptors. This study was designed to investigate if the differential expression of GABA receptor subunits α1/α4/γ2/δ across the postsynaptic sites could contribute to benzodiazepine resistance in patients with focal cortical dysplasia (FCD), the most common cause of drug resistant epilepsy in pediatric population. Differential gene and cellular expression of GABA receptor subunits α1, α4, γ2 and δ were evaluated and validated using qPCR and immunohistochemistry. Whole cell patch clamp studies were performed on pyramidal neurons of resected cortical FCD samples to measure the spontaneous GABA receptor activity. Upregulation of α4-and γ2-subunits containing GABA receptors were observed at both mRNA and protein level. α1-and δ-subunits containing GABA receptors did not show any significant changes. Flumazenil treatment did not affect the kinetics of GABAergic events in FCD; however, it significantly reduced the frequency and amplitude of spontaneous GABAergic activity in non-seizure control samples. Our results demonstrate the enhanced expression of α4-containing GABA receptors and GABAergic activity in pyramidal neurons which in turn may contribute to benzodiazepine resistance in FCD patients.