Diminished Neurosteroid Sensitivity of Synaptic Inhibition and Altered Location of the α4 Subunit of GABA_AReceptors in an Animal Model of Epilepsy

Abstract

In animal models of temporal lobe epilepsy (TLE), neurosteroid sensitivity of GABA A receptors on dentate granule cells (DGCs) is diminished; the molecular mechanism underlying this phenomenon remains unclear. The current study investigated a mechanism for loss of neurosteroid sensitivity of synaptic GABA A receptors in TLE. Synaptic currents recorded from DGCs of epileptic animals (epileptic DGCs) were less frequent, larger in amplitude, and less sensitive to allopregnanolone modulation than those recorded from DGCs of control animals (control DGCs). Synaptic currents recorded from epileptic DGCs were less sensitive to diazepam and had altered sensitivity to benzodiazepine inverse agonist RO 15-4513 (ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5␣][1,4]benzodiazepine-3-carboxylate) and furosemide than those recorded from control DGCs. Properties of synaptic currents recorded from epileptic DGCs appeared similar to those of recombinant receptors containing the ␣4 subunit. Expression of the ␣4 subunit and its colocalization with the synaptic marker GAD65 was increased in epileptic DGCs. Location of the ␣4 subunit in relation to symmetric (inhibitory) synapses on soma and dendrites of control and epileptic DGCs was examined with postembedding immunogold electron microscopy. The ␣4 immunogold labeling was present more commonly within the synapse in epileptic DGCs compared with control DGCs, in which the subunit was extrasynaptic. These studies demonstrate that, in epileptic DGCs, the neurosteroid modulation of synaptic currents is diminished and ␣4 subunit-containing receptors are present at synapses and participate in synaptic transmission. These changes may facilitate seizures in epileptic animals.

Alterations of GABAA-Receptor Function and Allosteric Modulation During Development of Status Epilepticus

“…It was shown that GABA A -receptor-mediated inhibition was reduced in the epileptic rats (Isokawa 1996;Kobayashi and Buckmaster 2003). Several other studies, interestingly, demonstrated that mIPSC amplitude was enhanced in these animals (Cohen et al 2003;Gavrilovici et al 2006;Leroy et al 2004;Nusser et al 1998;Sun et al 2007). In contrast to the possible mechanisms for the acute changes we observed, alterations of GABAergic phasic inhibition during epilepsy are likely related to long-term changes in GABA A -receptor expression and/or function such as regulation of receptor gene expression and degradation or synthesis of multiple receptor subunit proteins.…”

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

“…There is evidence showing that epilepsy models result in reduced expression of the ␦ subunit in the dentate gyrus (Zhang et al, 2007), although in a mouse model of temporal lobe epilepsy, ␣4 and ␥2 were increased (Peng et al, 2004). A marked decrease in neurosteroid sensitivity was observed in epileptic rats (Mtchedlishvili et al, 2001;Sun et al, 2007). High levels of ␦ expression, in contrast, would be expected to attenuate the seizure state.…”

Factors Related to Seizure in Tramadol Poisoning and Its Blood Concentration

“…Research indicates that in high concentrations tramadol exerts an inhibitory effect on gammaaminobutyric acid (GABA) receptors [12,13]. Inhibition of GABA receptors has been found to potentiate the severity of seizures in animal models [13,14]. In addition, GABA receptor inhibition induced by tramadol can be secondary to its opioid receptor agonist activity [13], and continuing this agonist activity on opioid receptor has been proven to precipitate seizure due to inhibition of GABA pathways [15,16].…”