Sequential Release of GABA by Exocytosis and Reversed Uptake Leads to Neuronal Swelling in Simulated Ischemia of Hippocampal Slices

Nicola J. Allen, David J. Rossi, David Attwell

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

GABA release during cerebral energy deprivation (produced by anoxia or ischemia) has been suggested either to be neuroprotective, because GABA will hyperpolarize neurons and reduce release of excitotoxic glutamate, or to be neurotoxic, because activation of GABAA receptors facilitates Cl - entry into neurons and consequent cell swelling. We have used the GABAA receptors of hippocampal area CA1 pyramidal cells to sense the rise of [GABA]o occurring in simulated ischemia. Ischemia evoked, after several minutes, a large depolarization to ∼ -20 mV. Before this "anoxic depolarization," there was an increase in GABA release by exocytosis (spontaneous IPSCs). After the anoxic depolarization, there was a much larger, sustained release of GABA that was not affected by blocking action potentials, vesicular release, or the glial GABA transporter GAT-3 but was inhibited by blocking the neuronal GABA transporter GAT-1. Blocking GABA A receptors resulted in a more positive anoxic depolarization but decreased cell swelling at the time of the anoxic depolarization. The influence of GABAA receptors diminished in prolonged ischemia because glutamate release evoked by the anoxic depolarization inhibited GABA A receptor function by causing calcium entry through NMDA receptors. These data show that ischemia releases GABA initially by exocytosis and then by reversal of GAT-1 transporters and that the resulting Cl- influx through GABAA receptor channels causes potentially neurotoxic cell swelling.

Original languageEnglish (US)
Pages (from-to)3837-3849
Number of pages13
JournalJournal of Neuroscience
Volume24
Issue number15
DOIs
StatePublished - Apr 14 2004
Externally publishedYes

Keywords

  • Chloride
  • Excitotoxicity
  • GABA
  • GAT-1
  • Ischemia
  • Reversed uptake
  • Transporter

ASJC Scopus subject areas

  • Neuroscience(all)

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