Pharmacological plasticity of GABA(A) receptors at dentate gyrus synapses in a rat model of temporal lobe epilepsy.
In the lithium-pilocarpine model (Li-pilocarpine) of temporal lobe epilepsy, GABA(A) receptor-mediated inhibitory postsynaptic currents (GABA(A) IPSCs) were recorded in dentate gyrus granule cells (GCs) from adult rat hippocampal slices. The properties of GABA(A) IPSCs were compared before and after superfusion of modulators in control conditions (Li-saline rats) and in Li-pilocarpine rats 24-48 h and 3-5 months (epileptic rats) after status epilepticus (SE). The mean peak amplitude of GABA(A) IPSCs increased by about 40% over Li-saline values in GCs 24-48 h after SE and remained higher in epileptic rats. In Li-pilocarpine rats, studied at 24-48 h after SE, diazepam (1 microm) lost 65% of its effectiveness at increasing the half-decay time (T(50%)) of GABA(A) miniature IPSCs (mIPSCs). Diazepam had no effects on mIPSC T(50%) in epileptic rats. The benzodiazepine ligand flumazenil (1 microm), acting as an antagonist in Li-saline rats, exhibited a potent inverse agonistic effect on GABA(A) mIPSCs of GCs from Li-pilocarpine rats 24-48 h and 3-5 months after SE. The neurosteroid allopregnanolone (100 nm), which considerably prolonged GABA(A) mIPSCs in Li-saline rats, totally lost its effect in rats studied 24-48 h after SE. However, this decrease in effectiveness was transient and was totally restored in epileptic rats. In addition to the up-regulation in the number of receptors at individual GC synapses, we propose that these 'epileptic' GABA(A) receptors possess benzodiazepine binding sites with altered allosteric properties. The failure of benzodiazepine and neurosteroid to potentiate inhibition early after SE may be a critical factor in the development of epileptogenesis and occurrence of seizures.
Leroy
Claire
C
Psychopathologie et Pharmacologie de la cognition, INSERM U405, Strasbourg, France.
Poisbeau
Pierrick
P
Keller
A Florence
AF
Nehlig
Astrid
A
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000503:physiopathology*; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004553:Electric Conductivity; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000503:physiopathology*; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D008094:Lithium; D008297:Male; D009433:Neural Inhibition; D018408:Patch-Clamp Techniques; D010862:Pilocarpine; D011280:Pregnanolone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013226:Status Epilepticus / Q000139:chemically induced / Q000503:physiopathology*; D013569:Synapses / Q000502:physiology*
D000927:Anticonvulsants; D018757:GABA Modulators; D011963:Receptors, GABA-A; D010862:Pilocarpine; D005442:Flumazenil; D008094:Lithium; D011280:Pregnanolone; D003975:Diazepam