Cytosolic phospholipase A2 alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment

Ying Shen, Koji Kishimoto, David J. Linden, Adam Sapirstein

Research output: Contribution to journalArticle

Abstract

The arachidonic acid-generating enzyme cytosolic phospholipase A 2 alpha (cPLA2α) has been implicated in the progression of excitotoxic neuronal injury. However, the mechanisms of cPLA 2α toxicity have yet to be determined. Here, we used a model system exposing mouse hippocampal slices to NMDA as an excitotoxic injury, in combination with simultaneous patch-clamp recording and confocal Ca2+ imaging of CA1 pyramidal neurons. NMDA treatment caused significantly greater injury in wild-type (WT) than in cPLA2α null CA1 neurons. Bath application of NMDA evoked a slow inward current in voltage-clamped neurons (composed of both NMDA receptor-mediated and other conductances) that was smaller in cPLA2α null than in WT slices. This was not due to down-regulation of NMDA receptor function because NMDA receptor-mediated currents were equivalent in each genotype following brief photolysis of caged glutamate. Current-clamp recordings were made during and following NMDA exposure by eliciting a single action potential with a brief current injection. After NMDA exposure, WT CA1 neurons developed a spike-evoked plateau potential and an increased spike-evoked dendritic Ca2+ transient. These effects were absent in CA1 neurons from cPLA2α null mice and WT neurons treated with a cPLA2α inhibitor. The Ca-sensitive K-channel toxins, apamin and paxilline, caused spike broadening and Ca2+ enhancement in WT and cPLA2α null slices. NMDA application in WT and arachidonate applied to cPLA2α null cells occluded the effects of apamin/paxilline. These results indicate that cPLA2α activity is required for development of aberrant electrophysiologic events triggered by NMDA receptor activation, in part through attenuation of K-channel function.

Original languageEnglish (US)
Pages (from-to)6078-6083
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number14
DOIs
StatePublished - Apr 3 2007

Keywords

  • Action potential
  • Arachidonic acid
  • Calcium
  • Excitotoxicity
  • Inhibition

ASJC Scopus subject areas

  • General

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