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J Physiol Volume 568, Number 3, 951-966, November 1, 2005 DOI: 10.1113/jphysiol.2005.094631
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Epileptiform activity triggers long-term plasticity of GABAB receptor signalling in the developing rat hippocampus

P Tosetti1,3, N Ferrand2, I. Colin-Le Brun2 and J. L Gaïarsa2

1 Institut de Génomique Fonctionnelle, CNRS UMR5203/INSERM U661/UM1/UM2, Montpellier, France
2 INMED, INSERM U29, Marseille, France

GABAB receptor (GABABR)-mediated presynaptic inhibition regulates neurotransmitter release from synaptic terminals. In the neonatal hippocampus, GABABR activation reduces GABA release and terminates spontaneous network discharges called giant depolarizing potentials (GDPs). Blocking GABABRs transforms GDPs into longer epileptiform discharges. Thus, GABABR-mediated presynaptic inhibition of GABA release (GABA auto-inhibition) controls both spontaneous network activity and excitability in the developing hippocampus. Here we show that extensive release of endogenous GABA during epileptiform activity impairs GABA auto-inhibition, but not GABABR-mediated inhibition of glutamate release, leading to hyperexcitability of the neonatal hippocampal network. Paired-pulse depression of GABA release (PPD) and heterosynaptic depression of glutamate release were used to monitor the efficacy of presynaptic GABABR-mediated inhibition in slices. PPD, but not heterosynaptic depression, was dramatically reduced after potassium (K+)-induced ictal-like discharges (ILDs), suggesting a selective impairment of GABABR-dependent presynaptic inhibition of GABAergic terminals. Impairing GABA auto-inhibition induced a 44% increase in GDP width and the appearance of pathological network discharges. Preventing GABA-induced activation of GABABRs during ILDs avoided PPD loss and most modifications of the network activity. In contrast, a partial block of GABABRs induced network discharges strikingly similar to those observed after K+-driven ILDs. Finally, neither loss of GABA auto-inhibition nor network hyperexcitability could be observed following synchronous release of endogenous GABA in physiological conditions (during GDPs at 1 Hz). Thus, epileptiform activity was instrumental to impair GABABR-dependent presynaptic inhibition of GABAergic terminals. In conclusion, our results indicate that endogenous GABA released during epileptiform activity can reduce GABA auto-inhibition and trigger pathological network discharges in the newborn rat hippocampus. Such functional impairment may play a role in acute post-seizure plasticity.

(Received 13 July 2005; accepted after revision 5 August 2005; first published online 11 August 2005)
Corresponding author P. Tosetti: IGF, 144 rue de la Cardonille, 34094, Montpellier cedex 05, France. Email: ptosetti{at}igf.cnrs.fr






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