Receptors with low affinity for neurosteroids and GABA contribute to tonic inhibition of granule cells in epileptic animals

Abstract

Neurosteroid sensitivity of GABAA receptor mediated inhibition of the hippocampal dentate granule cells (DGCs) is reduced in animal models of temporal lobe epilepsy. However, the properties and subunit composition of GABAA receptors mediating tonic inhibition in DGCS of epileptic animals have not been described. In the DGCs of epileptic animals, allopregnanolone and L-65708 sensitivity of holding current was diminished and δ subunit was retained in the endoplasmic reticulum and its surface expression was decreased the in the hippocampus. Ro15–4513 and lanthanum had distinct effects on holding current recorded from DGCs of control and epileptic animals. The pharmacological properties of GABAA receptors maintaining tonic inhibition in DGCs of epileptic animals were similar to those containing the α4βxγ2 subunits. Furthermore, surface expression of the α4 subunit increased and a larger fraction of the subunit was co-immunoprecipitated with the γ2 subunit in hippocampi of epileptic animals. Together these studies revealed that functional α4βxδ and α5βxγ2 receptors were reduced in the hippocampi of epileptic animals, and that novel α4bxγ2 receptors contributed to the maintenance of tonic inhibition. The presence of α4βxγ2 receptors resulted in low GABA affinity and neurosteroid sensitivity of tonic currents in the DGCs of epileptic animals that could potentially increase seizure vulnerability. These receptors may represent a novel therapeutic target for anticonvulsant drugs without sedative actions.

Estrous Cycle Regulation of Extrasynaptic δ-Containing GABAA Receptor-Mediated Tonic Inhibition and Limbic Epileptogenesis

“…To study the effect of GABA A R subunits, especially d-subunit plasticity on receptor function, we used patch-clamp electrophysiology to assess inhibitory currents in neurons. The effect of allosteric modulators on GABA A R function is markedly influenced by the presence of the d-subunit (Maguire et al, 2005;Mtchedlishvili and Kapur, 2006;Rajasekaran et al, 2010). We used electrophysiology to confirm d-subunit-specific pharmacological effects in the dissociated neurons during estrous cycle.…”

“…However, no significant difference was seen in the tonic conductance recorded in CA1PCs in diestrus compared with those in estrus. Perfusion of 3 mM GABA was used to model extracellular GABA concentration in vivo (Timmerman and Westerink, 1997;Shin et al, 2002;Rajasekaran et al, 2010), which is believed to activate selectively GABA A R-mediated tonic inhibition without largely altering synaptic currents; 3 mM GABA significantly increased tonic current (Fig. 6A).…”

Decrease in Tonic Inhibition Contributes to Increase in Dentate Semilunar Granule Cell Excitability after Brain Injury

“…Tonic inhibition can contribute substantially to resting membrane conductance and regulate neuronal gain and excitability (Mitchell and Silver, 2003;Ruiz et al, 2003;Chadderton et al, 2004;Farrant and Nusser, 2005). Receptors underlying granule cell tonic GABA currents are known to be altered in models of acquired epilepsy (Peng et al, 2004;Zhang et al, 2007;Zhan and Nadler, 2009;Rajasekaran et al, 2010), including cortical impact injury (Mtchedlishvili et al, 2010). However, whether the source of inhibitory inputs to SGCs is the same as that of granule cells, whether SGCs have tonic GABA currents, and if brain injury modifies synaptic and tonic inhibition in SGCs, is not known.…”

N-Methyl-D-Aspartic Acid Receptor Activation Downregulates Expression ofδSubunit-Containing GABAAReceptors in Cultured Hippocampal Neurons

“…In animal models of temporal lobe epilepsy, GABAR-d expression is diminished in the hippocampal DGCs (Peng et al, 2004;Zhang et al, 2007;Rajasekaran et al, 2010). In contrast, the expression of a4 subunits, which usually assemble with d subunits, is increased (Peng et al, 2004;Rajasekaran et al, 2010).…”

“…In contrast, the expression of a4 subunits, which usually assemble with d subunits, is increased (Peng et al, 2004;Rajasekaran et al, 2010). Reduction in GABAR-d is associated with diminished neurosteroid modulation of tonic currents; however, total tonic current is preserved (Zhang et al, 2007;Rajasekaran et al, 2010). Upregulation of the g2 subunit-containing receptors maintained tonic current and enhanced synaptic inhibition of the DGCs of epileptic s This article has supplemental material available at molpharm.aspetjournals.…”