Sustained Ca2+-induced Ca2+-release underlies the post-glutamate lethal Ca2+ plateau in older cultured hippocampal neurons

Gregory V. Clodfelter, Nada M. Porter, Philip W. Landfield, Olivier Thibault

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Several studies have shown that a prolonged Ca2+ elevation follows a glutamate-mediated excitotoxic insult in cultured neurons, and may be associated with impending cell death. Recently, we showed that the prolonged Ca2+ elevation that emerges as neurons age in culture is specifically linked to an age-related increase in excitotoxic vulnerability. However, the multiple sources of Ca2+ that contribute to Ca2+ elevation during and after glutamate exposure are not well understood. Here, we examined the Ca2+ sources of the age-related prolonged Ca2+ elevation in cultured hippocampal neurons. Studies with caffeine showed that the ryanodine receptor-dependent releasable pool of Ca2+ from intracellular stores was similar in older and younger neurons. Thapsigargin, which inhibits intracellular store refilling, did not mimic the age-related prolonged Ca2+ elevation and, in fact, partially reduced it. Ryanodine, which blocks Ca2+-induced Ca2+-release (CICR) from stores, completely blocked the age-related prolonged Ca2+ elevation following glutamate exposure but did not alter maximal Ca2+ elevation during the glutamate exposure. Thus, we conclude that sustained CICR plays a selective and key role in generating the lethal, age-related, prolonged Ca2+ elevation, and is the likely mechanism underlying age-related, enhanced vulnerability to excitotoxicity in neurons.

Original languageEnglish
Pages (from-to)189-200
Number of pages12
JournalEuropean Journal of Pharmacology
Issue number2-3
StatePublished - Jul 5 2002

Bibliographical note

Funding Information:
This work was supported by grants AG04542 and AG10836 from the National Institute on Aging. We thank Elsie Barr and Jeanise Staton for their invaluable technical assistance.

Copyright 2008 Elsevier B.V., All rights reserved.


  • Aging
  • Ca imaging
  • Caffeine
  • Endoplasmic reticulum
  • Excitotoxicity
  • Ryanodine
  • Thapsigargin

ASJC Scopus subject areas

  • Pharmacology


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