AN IN VITRO AND IN SILICO INVESTIGATION OF THE ROLE OF NMDA RECEPTOR SUBTYPES FOLLOWING MECHANICAL INJURY

The N-methyl D-aspartate receptor (NMDAR), a common glutamate receptor found throughout the brain, has long been implicated as the major mediator of the pathology seen after traumatic brain injury (TBI). However, given their critical role in physiologic function of neural networks, complete inhibition of these receptors is an unsuitable therapeutic strategy. Thus, further investigation into how these receptors respond to injury is required to identify more directed therapeutic targets. Here, we aimed to use two unique experimental models to further investigate the role of NMDARs in the neuronal response to TBI, with specific emphasis on the contribution of different NMDAR subtypes. TBI produces a unique disease paradigm containing mechanical and biochemical components, which can both affect NMDAR activity. We sought to isolate the effects of both these components and then to examine how they combine to create a unique injury response. We utilized a recombinant system expressing known NMDAR subtypes to first examine the action of mechanical stretch on specific subtypes. We demonstrated that mechanosensitivity of the NMDAR is indeed dependent on its subunit composition, with the NR2B subunit conferring stretch sensitivity. Further, we were able to investigate the regulation of NR2B mechanosensitivity and found that a single PKC phosphorylatio