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.


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

ASJC Scopus subject areas

  • Pharmacology


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