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 [electronic resource] /
Magdalini Sachana, Sharon Munn and Anna Bal-Price
- Paris : OECD Publishing, 2016.
- 118 p. ; 21 x 29.7cm.
- OECD Series on Adverse Outcome Pathways, no.6 2415170X ; .
- OECD Series on Adverse Outcome Pathways, no.6. .
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.