Role of β_2/3-specific GABA-A receptor isoforms in the development of hippocampus kindling epileptogenesis

Subunit-specific positive allosteric modulators (PAMs) of gamma-aminobutyric acid-A (GABA-A) receptors are commonly used to uncover the role of GABA-A receptor isoforms in brain function. Recently, we have designed novel PAMs selective for β_2/3-subunit containing GABA-A receptors (β_2/3-selective PAMs) that are nonbenzodiazepine site-mediated and do not show an α-subunit isoform selectivity, yet exhibit anxiolytic efficacy with reduced potential for sedation, cognitive impairment, and tolerance. In this study, we used three novel β_2/3-selective PAMs (2-261, 2-262, and 10029) with differential β_2/3-subunit potency to identify the role of β_2/3-selective receptor isoforms in limbic epileptogenesis.

Experimental epileptogenesis was induced in mice by daily hippocampus stimulations until each mouse showed generalized (stage 5) seizures. Patch-clamp electrophysiology was used to record GABA-gated currents. Brain levels of β_2/3-selective PAMs were determined for mechanistic correlations.

Treatment with the β_2/3-selective PAMs 2-261 (30mg/kg), 2-262 (10mg/kg), and 10029 (30mg/kg), 30min prior to stimulations, significantly suppressed the rate of development of kindled seizure activity without affecting the afterdischarge (AD) signal, indicating their disease-modifying activity. The β_2/3-selective agents suppressed chemical epileptogenesis in the pentylenetetrazol model. Test doses of these agents were devoid of acute antiseizure activity in the kindling model.

These findings demonstrate that β_2/3-selective PAMs can moderately retard experimental epileptogenesis, indicating the protective role of β_2/3-subunit GABA-A receptor isoforms in the development of epilepsy.