NMDA receptor-mediated excitotoxic neuronal apoptosis in vitro and in vivo occurs in an ER stress and PUMA independent manner

Caoimhín G. Concannon, Manus Ward, Helena P. Bonner, Katsura Kuroki, Liam P. Tuffy, Caroline T. Bonner, Ina Woods, Tobias Engel, David C. Henshall, Jochen H.M. Prehn

    Research output: Contribution to journalArticlepeer-review

    46 Scopus citations

    Abstract

    Disruption of endoplasmic reticulum (ER) Ca 2+ homeostasis and ER dysfunction have been suggested to contribute to excitotoxic and ischaemic neuronal injury. Previously, we have characterized the neural transcriptome following ER stress and identified the BH3-only protein, p53 up-regulated mediator of apoptosis (PUMA), as a central mediator of ER stress toxicity. In this study, we investigated the effects of excitotoxic injury on ER Ca 2+ levels and induction of ER stress responses in models of glutamate- and NMDA-induced excitotoxic apoptosis. While exposure to the ER stressor tunicamycin induced an ER stress response in cerebellar granule neurons, transcriptional activation of targets of the ER stress response, including PUMA, were absent following glutamate-induced apoptosis. Confocal imaging revealed no long-term changes in the ER Ca 2+ level in response to glutamate. Murine cortical neurons and organotypic hippocampal slice cultures from PUMA+/+ and PUMA-/- animals provided no evidence of ER stress and did not differ in their sensitivity to NMDA. Finally, NMDA-induced excitotoxic apoptosis in vivo was not associated with ER stress, nor did deficiency in PUMA alleviate the injury induced. Our data suggest that NMDA receptor-mediated excitotoxic apoptosis occurs in vitro and in vivo in an ER stress and PUMA independent manner.

    Original languageEnglish (US)
    Pages (from-to)891-903
    Number of pages13
    JournalJournal of Neurochemistry
    Volume105
    Issue number3
    DOIs
    StatePublished - May 1 2008

    Keywords

    • BH3-only protein
    • Endoplasmic reticulum stress
    • Excitotoxicity
    • Glutamate
    • NMDA

    ASJC Scopus subject areas

    • Biochemistry
    • Cellular and Molecular Neuroscience

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