Neuronal networks provide rapid neuroprotection against spreading toxicity

Andrew J. Samson, Graham Robertson, Michele Zagnoni, Christopher N. Connolly (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    15 Citations (Scopus)
    166 Downloads (Pure)

    Abstract

    Acute secondary neuronal cell death, as seen in neurodegenerative disease, cerebral ischemia (stroke) and traumatic brain injury (TBI), drives spreading neurotoxicity into surrounding, undamaged, brain areas. This spreading toxicity occurs via two mechanisms, synaptic toxicity through hyperactivity, and excitotoxicity following the accumulation of extracellular glutamate. To date, there are no fast-acting therapeutic tools capable of terminating secondary spreading toxicity within a time frame relevant to the emergency treatment of stroke or TBI patients. Here, using hippocampal neurons (DIV 15-20) cultured in microfluidic devices in order to deliver a localized excitotoxic insult, we replicate secondary spreading toxicity and demonstrate that this process is driven by GluN2B receptors. In addition to the modeling of spreading toxicity, this approach has uncovered a previously unknown, fast acting, GluN2A-dependent neuroprotective signaling mechanism. This mechanism utilizes the innate capacity of surrounding neuronal networks to provide protection against both forms of spreading neuronal toxicity, synaptic hyperactivity and direct glutamate excitotoxicity. Importantly, network neuroprotection against spreading toxicity can be effectively stimulated after an excitotoxic insult has been delivered, and may identify a new therapeutic window to limit brain damage.
    Original languageEnglish
    Article number33746
    Pages (from-to)1-11
    Number of pages11
    JournalScientific Reports
    Volume6
    DOIs
    Publication statusPublished - 21 Sep 2016

    Keywords

    • Cell death in the nervous system
    • Cellular neuroscience
    • Inhibition-excitation balance
    • Neural circuits
    • Stroke

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  • Student Theses

    Rapid neuronal responses during spreading neurotoxic and neuroprotective network activity

    Author: Samson, A. J., 2016

    Supervisor: Connolly, C. (Supervisor) & Langston, R. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

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