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Pharmacological plasticity of GABA_\textrmA receptors at dentate gyrus synapses in a rat model of temporal lobe epilepsy
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International audience. 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 μ m ) 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 μ m ), 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 n m ), 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.
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