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bioRxiv · 10.1101/2022.01.03.474836

Long-term dynamic changes of NMDA receptors following an excitotoxic challenge

Granzotto, A.·d'Aurora, M.·Bomba, M.·Gatta, V.·Onofrj, M.·Sensi, S. L.
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Abstract

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons [also known as nNOS (+) neurons] are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a key divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we demonstrate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.

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Granzotto, A., d'Aurora, M., Bomba, M., Gatta, V., Onofrj, M., Sensi, S. L.. 2022-01-03. Long-term dynamic changes of NMDA receptors following an excitotoxic challenge. https://doi.org/10.1101/2022.01.03.474836

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