Kutzing, Melinda Karen. Development of an in vitro tool to measure the function of neurons protected from glutamate-induced excitotoxicity. Retrieved from https://doi.org/doi:10.7282/T32806PX
DescriptionTraumatic brain injury (TBI) results in devastating neurological damage that affects millions of individuals each year. TBI occurs as a result of an external physical insult that leads to mechanical injury followed by a cascade of secondary chemical insults that develop over a period of hours to days, damaging cells and tissue further removed from the initial site of injury. Often, this secondary injury leads to more significant clinical impairments and may ultimately be the deciding factor in the patient’s recovery. There remains a tremendous need to develop therapeutics that interfere with secondary injury mechanisms to protect neural function. The development of appropriate models of TBI is one of the primary hurdles in this field. Expensive in vivo animal models focus on behavioral endpoints and have resulted in only moderate improvements in patient outcomes. Most of the current in vitro models of TBI rely on endpoints, such as cell morphology or biochemistry that do not necessarily correlate with cell function. While preservation of cell number and cell morphology are necessary for a positive outcome after TBI, the cells must also be able to send and receive signals as they did before the injury occurred in order for the central nervous system (CNS) to function properly. The objective of this thesis is to develop an in vitro model of TBI that can measure changes in the function of cells following injury. Using microelectrode arrays (MEAs) to study TBI enables one to record the cellular activity before and after injury and with treatment and allows for the measurement of changes in the patterns of electrical activity within the neuronal network, providing a clear picture of not only whether the cells have survived but also how they function. Our results show that we are able to detect changes in neuronal function that are not detected using simpler in vitro models. Additionally, we investigated the ability of memantine, an uncompetitive NMDA receptor inhibitor, to protect against secondary injury mechanisms. Using this tool to screen other potential neuroprotective compounds and identify those that can preserve cell function may translate to better success in animal models.