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Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

Author

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  • Magdalini Sachana

    (Joint Research Centre, European Commission, Ispra)

  • Sharon Munn

    (Joint Research Centre, European Commission, Ispra)

  • Anna Bal-Price

    (Joint Research Centre, European Commission, Ispra)

Abstract

Under physiological conditions activation of glutamate ionotropic receptors such as N-methyl-D-aspartate (NMDARs), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPARs) and kainate (KARs) is responsible for basal excitatory synaptic transmission and synaptic plasticity. However, sustained over-activation of these receptors can induce excitotoxic neuronal cell death. Increased Ca2+ influx through NMDARs promotes many pathways of toxicity due to generation of free radical species, reduced ATP production, endoplasmic reticulum (ER) stress and protein aggregation. Neuronal injury induced by over-activation of these receptors and the excessive Ca2+ influx is considered an early key event of excitotoxicity. The proposed AOP is relevant to adult neurotoxicity. The MIE has been defined as a direct binding of agonists to NMDARs or indirect, through prior activation of AMPARs and/or KARs resulting in sustained NMDARs over-activation causing excitotoxic neuronal cell death, mainly in hippocampus and cortex, two brain structures fundamental for learning and memory processes.

Suggested Citation

  • Magdalini Sachana & Sharon Munn & Anna Bal-Price, 2016. "Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairm," OECD Series on Adverse Outcome Pathways 6, OECD Publishing.
  • Handle: RePEc:oec:envaad:6-en
    DOI: 10.1787/5jlr8vqgm630-en
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    Keywords

    adult neurotoxicity; excitotoxicity; impairment of learning and memory in adults; ionotropic glutamate receptors;
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