Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABA_A receptors

Background: GABAergic deficit is one of the major mechanisms underlying epileptic seizures. Previous studies have mainly focused on alterations of synaptic GABAergic inhibition during epileptogenesis. Recent work suggested that tonic inhibition may also play a role in regulating epileptogenesis, but the underlying mechanism is not well understood. Results: We employed molecular and pharmacological tools to investigate the role of tonic inhibition during epileptogenesis both in vitro and in vivo. We overexpressed two distinct subtypes of extrasynaptic GABA_A receptors, 5β3γ2 and 6β3δ receptors, in cultured hippocampal neurons. We demonstrated that overexpression of both 5β3γ2 and 6β3δ receptors enhanced tonic inhibition and reduced epileptiform activity in vitro. We then showed that injection of THIP (5 μM), a selective agonist for extrasynaptic GABA _A receptors at low concentration, into rat brain also suppressed epileptiform burst activity and behavioral seizures in vivo. Mechanistically, we discovered that low concentration of THIP had no effect on GABAergic synaptic transmission and did not affect the basal level of action potentials, but significantly inhibited high frequency neuronal activity induced by epileptogenic agents. Conclusions: Our studies suggest that extrasynaptic GABA_A receptors play an important role in controlling hyperexcitatory activity, such as that during epileptogenesis, but a less prominent role in modulating a low level of basal activity. We propose that tonic inhibition may play a greater role under pathological conditions than in physiological conditions in terms of modulating neural network activity.