GABA_A receptor function in epileptic human dentate granule cells: comparison to epileptic and control rat

Abstract 

Using patch clamp recording techniques in dentate granule cells (DGCs) isolated from patients undergoing temporal lobectomy for intractable epilepsy, we investigated basic properties of GABA_A receptors (GABA_ARs) and pharmacological sensitivity of GABA-evoked currents to modulation by zinc and benzodiazepines (BZ). Properties of human DGC GABA_ARs were compared to DGC GABA_AR properties in control and epileptic rats. Blockade of GABA evoked currents by zinc was significantly enhanced in epileptic human relative to control rat DGCs. Augmentation of the GABA_AR current by the non-subunit selective BZ agonist, clonazepam (CNZ) and by the BZ₁ specific agonist, zolpidem (ZOL), were not significantly different in human DGCs relative to control or epileptic rat. GABA potency was significantly higher in epileptic human DGCs than in control or epileptic rat DGCs. The significantly enhanced efficacy of zinc in blocking GABA currents in epileptic human DGCs mirrors that seen in epileptic rat DGCs, and was coupled with mossy fiber sprouting evident in both epileptic human and rat dentate gyrus. The aberrant mossy fibers provide a novel zinc delivery system within the epileptic dentate gyrus. The mossy fiber release of zinc onto DGCs coupled with the enhanced zinc sensitivity of GABA_ARs in epileptic DGCs, may lead to `dynamic disinhibition' which could compromise inhibitory efficacy in the epileptic rat and human hippocampus.

Keywords:  Hippocampus, Epilepsy, Seizures, Zinc, Patch clamp, Benzodiazepine, Sprouting