Role of brain mechanosensors on outcome after traumatic brain injury

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

? DESCRIPTION (provided by applicant): Finding precise reasons why some patients take much longer to recover from a mild traumatic brain injury (TBI) and why some brains are more vulnerable to rapid head rotation or impact will significantly improve our ability to identify at-rsk populations for TBI and help patients safely recover from these injuries. Our past work showed us the GluN2B subunit of the NMDA receptor confers a `force sensing' property to the receptor, and we determined this feature is controlled by phosphorylation of a serine residue on the GluN2B receptor subunit. We use these past findings to ask a broad question - does the GluN2B-based NMDAR mechanosensitivity provide a biomechanics-based reason for susceptibility and vulnerability of the brain to TBI? Our goal in this R21 proposal is to develop the transgenic tools to answer this question. To this end, we hypothesize that transgenic animals with reduced NMDAR mechanosensitivity will show a significant reduction in cognitive deficits and neuronal degeneration after both a single and repeated TBI. Our proposal examines this hypothesis in two aims: Aim 1: To test if GluN2B-S1323 site mutation affects neural development, behavior, hippocampal function, and neural architecture. Aim 2: To study if animals with mutations in the GluN2B subunit show improved (NMDA1323A) or worse (NMDA1323E) outcome after experimental TBI. We expect NMDAM1323A and NMDA1323E mice will develop normally and exhibit normal cognitive functions. However, because they have significantly reduced `force sensing' ability, NMDA1323A mice will show significantly less cognitive deficits and faster recovery after mild TBI. Conversely, NMDA1323E mice will show enhanced deficits following TBI. Impact: To our knowledge, this work will be the first to change the biomechanics of brain trauma at the molecular level. We expect two broad scientific themes emerging from this work. First, we would be positioned to examine epigenetic factors that enhance the expression of the GluN2B subunit, lending individuals more susceptible to TBI. Second, we would test the possibility that expression of the force-sensitive GluN2B subunit makes the recovering brain more vulnerable to a second injury.