Kainic acid-induced seizures enhance dentate gyrus inhibition by downregulation of GABAB receptors

Kurt Z. Haas, Ellen F. Sperber, Solomon L. Moshé, Patric K. Stanton

Research output: Contribution to journalArticle

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Abstract

Seizures cause a persistent enhancement in dentate synaptic inhibition concurrent with, and possibly compensatory for, seizure-induced hippocampal hyperexcitability. To study this phenomenon, we evoked status epilepticus in rats with systemic kainic acid (KA), and 2 weeks later assessed granule cell inhibition with paired-pulse stimulation of the perforant path (PP) in vitro. Controls demonstrated three components of paired-pulse inhibition: early inhibition (10-30 msec), intermediate facilitation (30-120 msec), and late inhibition (120 msec to 120 sec). After seizures, inhibition in all components was enhanced significantly. The GABAA antagonist bicuculline blocked only early enhanced inhibition, demonstrating that both GABAA and GABAB postsynaptic receptors contribute to seizure-induced enhanced inhibition. In controls, the GABAB antagonist CGP 35348 increased both GABAA and GABAB responses in granule cells, suggesting that CGP 35348 acts presynaptically, blocking receptors that suppress GABA release. In contrast, slices from KA-treated rats were markedly less sensitive to CGP 35348. To test the hypothesis that GABAB receptors regulating GABA release are downregulated after seizures, we measured paired-pulse suppression of recurrent IPSPs, or disinhibition, using mossy fiber stimuli. Early disinhibition (< 200 msec) was reduced after seizures, whereas late disinhibition remained intact. CGP 35348 blocked the early component of disinhibition in controls and, to a lesser extent, reduced disinhibition in KA slices. However, paired monosynaptic IPSPs recorded intracellularly showed no difference in disinhibition between groups. Our findings indicate that seizure-induced enhancement in dentate inhibition is caused, at least in part, by reduced GABAB function in the polysynaptic recurrent inhibitory circuit, resulting in reduced disinhibition and heightened GABA release.

Original languageEnglish (US)
Pages (from-to)4250-4260
Number of pages11
JournalJournal of Neuroscience
Volume16
Issue number13
Publication statusPublished - Dec 1 1996

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Keywords

  • Autoreceptors
  • Bicuculline
  • CGP 35348
  • Dentate gyrus
  • Disinhibition
  • Epilepsy
  • GABA
  • Hippocampus
  • Kainic acid
  • Paired-pulse inhibition
  • Presynaptic
  • Seizures

ASJC Scopus subject areas

  • Neuroscience(all)

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