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Cytosolic phospholipase A2 alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment.
Proc Natl Acad Sci U S A. 2007 Mar 26;
Authors: Shen Y, Kishimoto K, Linden DJ, Sapirstein A
The arachidonic acid-generating enzyme cytosolic phospholipase A2 alpha (cPLA2alpha) has been implicated in the progression of excitotoxic neuronal injury. However, the mechanisms of cPLA2alpha 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 Ca(2+) imaging of CA1 pyramidal neurons. NMDA treatment caused significantly greater injury in wild-type (WT) than in cPLA2alpha 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 cPLA2alpha 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 Ca(2+) transient. These effects were absent in CA1 neurons from cPLA2alpha null mice and WT neurons treated with a cPLA2alpha inhibitor. The Ca-sensitive K-channel toxins, apamin and paxilline, caused spike broadening and Ca(2+) enhancement in WT and cPLA2alpha null slices. NMDA application in WT and arachidonate applied to cPLA2alpha null cells occluded the effects of apamin/paxilline. These results indicate that cPLA2alpha activity is required for development of aberrant electrophysiologic events triggered by NMDA receptor activation, in part through attenuation of K-channel function.
PMID: 17389392 [PubMed - as supplied by publisher]
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