The use of a novel in vitro microfluidic model to understand how neurons in a network work together to respond to a local injury.

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 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 in clinical emergency situations.

The current project will investigate the mechanisms responsible for this fast-acting network activity, including the role of inhibition and rapid morphological responses that are unique reactions to rapid network communication following an injury.

Samson, AJ, Robertson G, Zagnoni, M & Connolly, CN. (2016). Neuronal networks provide rapid neuroprotection against spreading toxicity. Nature Scientific Reports (in press).


Upper second class degree or equivalent

Dr Chris Connolly
Subject Area: 
View all PhD opportunities in Division: