Mitochondrial control of acute glutamate excitotoxicity in cultured cerebellar granule cells

Roger F. Castilho, Oskar Hansson, Manus W. Ward, Samantha L. Budd, David G. Nicholls*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

183 Scopus citations


Mitochondria within cultured rat cerebellar granule cells have a complex influence on cytoplasmic free Ca2+ ([Ca2+](c)) responses to glutamate. A decreased initial [Ca2+](c) elevation in cells whose mitochondria are depolarized by inhibition of the ATP synthase and respiratory chain (conditions which avoid ATP depletion) was attributed to enhanced Ca2+ extrusion from the cell rather than inhibited Ca2+ entry via the NMDA receptor. Even in the presence of elevated extracellular Ca2+, when [Ca2+](c) responses were restored to control values, such cells showed resistance to acute excitotoxicity, defined as a delayed cytoplasmic Ca2+ deregulation (DCD) during glutamate exposure. DCD was a function of the duration of mitochondrial polarization in the presence of glutamate rather than the total period of glutamate exposure. Once initiated, DCD could not be reversed by NMDA receptor inhibition. In the absence of ATP synthase inhibition, respiratory chain inhibitors produced an immediate Ca2+ deregulation (ICD), ascribed to an ATP deficit. In contrast to DCD, ICD could be reversed by subsequent ATP synthase inhibition with or without additional NMDA receptor blockade. DCD could not be ascribed to the failure of an ATP yielding metabolic pathway. It is concluded that mitochondria can control Ca2+ extrusion from glutamate-exposed granule cells by the plasma membrane in three ways: by competing with efflux pathways for Ca2+, by restricting ATP supply, and by inducing a delayed failure of Ca2+ extrusion. Inhibitors of the mitochondrial permeability transition only marginally delayed the onset of DCD.

Original languageEnglish (US)
Pages (from-to)10277-10286
Number of pages10
JournalJournal of Neuroscience
Issue number24
StatePublished - Dec 15 1998
Externally publishedYes


  • Calcium
  • Excitotoxicity
  • Glutamate
  • Granule cell
  • Mitochondria
  • NMDA

ASJC Scopus subject areas

  • General Neuroscience


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