Acute desensitization of presynaptic GABA(B)-mediated inhibition and induction of epileptiform discharges in the neonatal rat hippocampus

P Tosetti, R Bakels, I Colin-Le Brun, N Ferrand, J L Gaiarsa, O Caillard*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    18 Citations (Scopus)

    Abstract

    The consequences of sustained activation of GABA(B) receptors on GABA(B)-mediated inhibition and network activity were investigated in the neonatal rat hippocampus using whole-cell and extracellular field recordings. GABA(B)-mediated presynaptic control of gamma-aminobutyric acid (GABA) release progressively diminished with time in spite of the continued presence of the agonist (100 muM baclofen, 15 min), indicating acute desensitization of presynaptic GABA(B)-mediated inhibition on GABAergic terminals. By contrast, neither GABA(B)-mediated inhibition of glutamate release nor postsynaptic GABA(B)-mediated inhibition seemed to produce this desensitization. Efficacy of presynaptic GABA(B) receptors was still reduced by 49% 30 min after baclofen washout, suggesting a long timeframe for recovery from desensitization. The 15-min baclofen application was followed by a dramatic modification of the spontaneous network activity, with the occurrence of epileptiform events called ictal-like discharges (ILDs). Extracellular field recordings confirmed the epileptic nature of the discharges that could be recorded up to 4 h after baclofen washout. ILDs did not occur when the GABA(B) receptor antagonist CGP35348 was coapplied with baclofen. This indicates that ILD induction is a consequence of the sustained activation of GABA(B) receptors and the correlated changes in GABA(B)-mediated inhibition. Furthermore, ILDs were also induced when blocking with CGP35348 an amount of GABA(B) receptors that exactly mimicked the loss of inhibition obtained with desensitization. These results show that presynaptic GABA(B)-mediated inhibition of GABA release acutely and specifically desensitizes following a sustained application of the GABA(B) receptor agonist baclofen. Conditions that induce desensitization of the GABA(B)-mediated responses also trigger persistent epileptiform discharges in the neonatal rat hippocampus.

    Original languageEnglish
    Pages (from-to)3227-3234
    Number of pages8
    JournalEuropean Journal of Neuroscience
    Volume19
    Issue number12
    DOIs
    Publication statusPublished - Jun-2004

    Keywords

    • baclofen
    • desensitization
    • development
    • epilepsy
    • GABA(B)
    • hippocampus
    • PROTEIN-COUPLED RECEPTORS
    • GABA-B RECEPTORS
    • IN-VITRO
    • KINASE-C
    • BACLOFEN
    • NEURONS
    • MECHANISMS
    • SEIZURES
    • SLICE
    • POTENTIALS

    Cite this