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Epileptogenesis causes an N-methyl-d-aspartate receptor/Ca2+-dependent decrease in Ca2+/calmodulin-dependent protein

Robert E Blair1, Sompong Sombati, Severn B Churn

  • 1Department of Neurology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298-0599, United States. rblair@vcu.edu

European Journal of Pharmacology
|May 23, 2008
PubMed

Insights

This study reveals that Ca2+/N-methyl-d-aspartate (NMDA) receptor activation mediates the decrease in CaM kinase II activity during low magnesium-induced epilepsy models, potentially contributing to seizure maintenance.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Epilepsy Research

Background:

  • Alterations in Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) function are implicated in epileptogenesis.
  • The precise molecular mechanisms linking epilepsy to CaM kinase II dysfunction remain unclear.

Purpose of the Study:

  • To investigate the molecular pathways responsible for reduced CaM kinase II activity in a hippocampal culture model of low magnesium-induced spontaneous recurrent epileptiform discharges (SREDs).

Main Methods:

  • Utilized a low Mg2+ hippocampal neuronal culture model to induce SREDs.
  • Assessed CaM kinase II activity via substrate phosphorylation (autocamtide-2).
  • Examined the role of Ca2+ levels, NMDA receptors, AMPA/kainate receptors, and L-type Ca2+ channels using specific antagonists and reduced extracellular Ca2+.

Main Results:

  • Low Mg2+-induced SREDs significantly decreased CaM kinase II-dependent substrate phosphorylation.
  • Reducing extracellular Ca2+ or adding APV (NMDA receptor antagonist) blocked this decrease.
  • AMPA/kainate receptor antagonists and L-type Ca2+ channel blockers did not affect the CaM kinase II activity reduction.

Conclusions:

  • The reduction in CaM kinase II activity during low Mg2+-induced SREDs is mediated by a selective Ca2+/NMDA receptor-dependent pathway.
  • This mechanism may play a role in the generation and persistence of SREDs in this epilepsy model.

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