Differential Epilepsy-Associated Alterations in Postsynaptic GABA_A Receptor Function in Dentate Granule and CA1 Neurons

Abstract

Alterations in GABAergic function associated with the development of temporal lobe epilepsy (TLE) were examined with the use of patch-clamp recording techniques in dentate granule (DG) and CA1 neurons acutely isolated from control and spontaneously epileptic rats in which TLE was elicited by pilocarpine injection 3-17 wk before use. The maximal efficacy of gamma-aminobutyric acid (GABA) in activating whole cell GABA currents increased significantly in epileptic DG neurons relative to controls. This efficacy increase was due to a 78% enhancement in the functional capacitance-normalized GABA(A) receptor (GABA(A)R) current density in epileptic DG neurons. Increased DG GABA(A)R current density was not accompanied by alterations in GABA potency (EC50). However, the maximal sensitivity of DG GABA-evoked currents to blockade by zinc increased 190% in epileptic neurons. Augmentation of epileptic DG neuron GABA-evoked currents by the broad-spectrum anticonvulsant benzodiazepine clonazepam (100 nM) was enhanced 114% relative to controls, whereas augmentation by the benzodiazepine, (BZ1)-selective agonist zolpidem (100 nM) was decreased by 66%. In contrast to DG neurons, maximal efficacy of GABA in activating GABA currents decreased in epileptic CA1 neurons relative to controls, due to a 52% decrease in functional capacitance-normalized GABA(A)R current density. This altered efficacy of GABA was accompanied by an increased GABA potency (GABA EC50 was 35.8 and 24.5 microM in control and epileptic neurons, respectively). Sensitivity of GABA-evoked currents to blockade by zinc was unchanged in epileptic CA1 neurons, whereas clonazepam (100 nM) augmentation of CA1 GABA-evoked currents decreased 81% relative to controls. These regionally distinct epilepsy-associated modifications in hippocampal GABAergic function may be due to discrete structural alterations in postsynaptic GABA(A)Rs accompanying epileptogenesis, could be therapeutically important, and undoubtedly could contribute to the enhanced limbic excitability underlying TLE.

Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA A receptor α4 subunit expression

“…At 2 weeks after virus injections, a subset of rats was exposed to PILO-induced SE according to a standard protocol (6,24). PILO injection triggered long-duration (Ͼ30 min) seizures within 10-30 min after injection.…”

Massive and Specific Dysregulation of Direct Cortical Input to the Hippocampus in Temporal Lobe Epilepsy

“…All experiments were performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and with the approval of the Children's Hospital of Philadelphia Institutional Animal Care and Use Committee. Pilocarpine animals were produced using previously reported methods (Gibbs et al, 1997). Adult male Sprague Dawley rats (180 -200 g) were pretreated with scopolamine methyl nitrate (1 mg/kg, s.c.) to antagonize peripheral effects induced by subsequent pilocarpine (405 mg/kg, s.c.), injected 30 min later.…”

“…Breakdown of the dentate "gate" has been hypothesized to be a primary contributor to seizure generation in epilepsy (Sutula et al, 1988;Heinemann et al, 1992;Lothman et al, 1992;Mello et al, 1993). Paradoxically, several TLE studies have indicated that inhibition within the dentate remains operative, and suppresses seizure propagation from the entorhinal cortex (Gibbs et al, 1997;Wilson et al, 1998;Wu and Leong 2001;Sloviter et al, 2006). Despite the controversy concerning the state of gate function of the dentate gyrus and disrupted intrinsic circuitry, the hippocampus remains critical in seizure generation.…”

Phosphatase inhibitors remove the run-down of γ-aminobutyric acid type A receptors in the human epileptic brain

“…Whereas some forms of epilepsy have been associated with mutations in genes coding for ion channels and ␥-aminobutyric acid (GABA) receptors (1,2); there is no clear genetic background in the refractory TLE patients. Nevertheless, there are clear associations to changes in metabolite concentrations (3), modifications in the properties of receptor and transporter systems of excitatory and inhibitory amino acid neurotransmitters (4 -6), changes in signaling proteins of postsynaptic densities (7), altered expression of neurotransmitter receptors (6,8,9), and altered GABA activity (10,11). Thus, epileptogenesis, extensively investigated in both animal models and humans, may be related to many events, including GABA type A receptor (GABA A -receptor) dysfunction (12).…”