Inability to restore resting intracellular calcium levels as an early indicator of delayed neuronal cell death

David D. Limbrick, Severn B. Churn, Sompong Sombati, Robert J. DeLorenzo

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

The hippocampus is especially vulnerable to excitotoxicity and delayed neuronal cell death. Chronic elevations in free intracellular calcium concentration ([Ca2+]i) following glutamate-induced excitotoxicity have been implicated in contributing to delayed neuronal cell death. However, no direct correlation between delayed cell death and prolonged increases in [Ca2+]i has been determined in mature hippocampal neurons in culture. This investigation was initiated to determine the statistical relationship between delayed neuronal cell death and prolonged increases in [Ca2+]i in mature hippocampal neurons in culture. Using indo-1 confocal fluorescence microscopy, we observed that glutamate induced a rapid increase in [Ca2+]i that persisted after the removal of glutamate. Following excitotoxic glutamate exposure, neurons exhibited prolonged increases in [Ca2+]i, and significant delayed neuronal cell death was observed. The N-methyl-D-aspartate (NMDA) channel antagonist MK-801 blocked the prolonged increases in [Ca2+]i and cell death. Depolarization of neurons with potassium chloride (KCl) resulted in increases in [Ca2+]i, but these increases were buffered immediately upon removal of the KCl, and no cell death occurred. Linear regression analysis revealed a strong correlation (R = 0.973) between glutamate-induced prolonged increases in [Ca2+]i and delayed cell death. These data suggest that excitotoxic glutamate exposure results in an NMDA-induced inability to restore resting [Ca2+]i (IRRC) that is a statistically significant indicator of delayed neuronal cell death.

Original languageEnglish
Pages (from-to)145-156
Number of pages12
JournalBrain Research
Volume690
Issue number2
DOIs
StatePublished - Sep 4 1995
Externally publishedYes

Keywords

  • Cell culture
  • Confocal microscopy
  • Excitotoxicity
  • Glutamate
  • Indo-1
  • NMDA

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