title: Neuronal networks provide rapid neuroprotection against spreading toxicity.
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.
authors.affiliation: Division of Neuroscience, School of Medicine, University of Dundee, Dundee, DD1 9SY, Scotland, Uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Samson
authors.affiliation: Centre for Microsystems and Photonics, Department of Electronic and Electrical Engineering, University of Strathclyde, Glasgow, G1 1XW, Scotland, Uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Robertson
authors.affiliation: Centre for Microsystems and Photonics, Department of Electronic and Electrical Engineering, University of Strathclyde, Glasgow, G1 1XW, Scotland, Uk.
authors.forename: Michele
authors.initials: M
authors.lastname: Zagnoni
authors.affiliation: Division of Neuroscience, School of Medicine, University of Dundee, Dundee, DD1 9SY, Scotland, Uk.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Connolly
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009415:Nerve Net / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000066829:Neuroprotection; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology