Lack of kainic acid-induced gamma oscillations predicts subsequent CA1 excitotoxic cell death

Seiichiro Jinde, Juan E. Belforte, Jun Yamamoto, Matthew A. Wilson, Susumu Tonegawa, Kazu Nakazawa

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Gamma oscillations are a prominent feature of hippocampal network activity, but their functional role remains debated, ranging from mere epiphenomena to being crucial for information processing. Similarly, persistent gamma oscillations sometimes appear prior to epileptic discharges in patients with mesial temporal sclerosis. However, the significance of this activity in hippocampal excitotoxicity is unclear. We assessed the relationship between kainic acid (KA)-induced gamma oscillations and excitotoxicity in genetically engineered mice in which N-methyl-d-aspartic acid receptor deletion was confined to CA3 pyramidal cells. Mutants showed reduced CA3 pyramidal cell firing and augmented sharp wave-ripple activity, resulting in higher susceptibility to KA-induced seizures, and leading to strikingly selective neurodegeneration in the CA1 subfield. Interestingly, the increase in KA-induced γ-aminobutyric acid (GABA) levels, and the persistent 30-50-Hz gamma oscillations, both of which were observed in control mice prior to the first seizure discharge, were abolished in the mutants. Consequently, on subsequent days, mutants manifested prolonged epileptiform activity and massive neurodegeneration of CA1 cells, including local GABAergic neurons. Remarkably, pretreatment with the potassium channel blocker α-dendrotoxin increased GABA levels, restored gamma oscillations, and prevented CA1 degeneration in the mutants. These results demonstrate that the emergence of low-frequency gamma oscillations predicts increased resistance to KA-induced excitotoxicity, raising the possibility that gamma oscillations may have potential prognostic value in the treatment of epilepsy.

Original languageEnglish (US)
Pages (from-to)1036-1055
Number of pages20
JournalEuropean Journal of Neuroscience
Volume30
Issue number6
DOIs
StatePublished - Sep 1 2009

Keywords

  • CA3
  • Epilepsy research
  • GABA
  • Mouse
  • NMDA receptors

ASJC Scopus subject areas

  • Neuroscience(all)

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