Altered expression of GABAA and GABAB receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus

T. Nishimura, C. Schwarzer, E. Gasser, N. Kato, A. Vezzani, G. Sperk

Research output: Contribution to journalArticle

Abstract

Epilepsy may result from altered transmission of the principal inhibitory transmitter GABA in the brain. Using in situ hybridization in two animal models of epileptogenesis, we investigated changes in the expression of nine major GABAA receptor subunits (α1, α2, α4, α5, β1-β3, γ2 and δ) and of the GABAB receptor species GABABR1a, GABABR1b and GABABR2 in 1) hippocampal kindling and 2) epilepsy following electrically-induced status epilepticus (SE). Hippocampal kindling triggers a decrease in seizure threshold without producing spontaneous seizures and hippocampal damage, whereas the SE model is characterized by spontaneous seizures and hippocampal damage. Changes in the expression of GABAA and GABAB receptor mRNAs were observed in both models, and compared with those seen in other models and in human temporal lobe epilepsy. The most prominent changes were a relatively fast (24 h after kindling and electrically-induced SE) and lasting (7 and 30 days after termination of kindling and SE, respectively) reduction of GABA A receptor subunit δ mRNA levels (by 43-78%) in dentate granule cells, accompanied by increases in mRNA levels of all three β-subunits (by 8-79%) and subunit γ2 (by 11-43%). Levels of the minor subunit α4 were increased by up to 60% in dentate granule cells in both animal models, whereas those of subunit α5 were decreased 24 h and 30 days after SE, but not after kindling. In cornu ammonis 3 pyramidal cells, downregulation of subunits α2, α4, α5, and β1-3 was observed in the ventral hippocampus and of α2, α5, β3 and γ2 in its dorsal extension 24 h after SE. Similar but less pronounced changes were seen in sector cornu ammonis 1. Persistent decreases in subunit α2, α4 and β2 transcript levels were presumably related to SE-induced cell loss. GABA B receptor expression was characterized by increases in GABA BR2 mRNA levels at all intervals after kindling and SE. The observed changes suggest substantial and cell specific rearrangement of GABA receptors. Lasting downregulation of subunits δ and α5 in granule cells and transient decreases in subunit α2 and β1-3 mRNA levels in cornu ammonis 3 pyramidal cells are suggestive of impaired GABAA receptor-mediated inhibition. Persistent upregulation of subunits β1-3 and γ2 of the GABAA receptor and of GABABR2 mRNA in granule cells, however, may result in activation of compensatory anticonvulsant mechanisms.

Original languageEnglish
Pages (from-to)691-704
Number of pages14
JournalNeuroscience
Volume134
Issue number2
DOIs
Publication statusPublished - 2005

Keywords

  • Hippocampus
  • Inhibitory neurotransmission
  • Seizures
  • Temporal lobe epilepsy

ASJC Scopus subject areas

  • Neuroscience(all)

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