| In an effort to find new and innovative therapies, we proposed 3 criteria for drug targets: novel target, relatively inactive in normal physiological function, and must effectively prevent the cell death associated with deficits following TBI. Since many of the therapies tested clinically were halted due to high levels of side effects, our criterion present a good goal with a relatively high probability of being efficacious in the treatment of TBI. To this point, choosing the often studied targets of global NMDAR or AMPAR would not provide the specificity and low side effect level that is desired. Finding a population of receptors the appear after in jury and play a detrimental role in the viability of crucial cell populations involved in activities such as learning, memory, and executive function would be ideal.;With these goals in mind, we looked to a possible new population of AMPARs and the mechanisms leading to their modification and trafficking. Following injury we found that there was a synaptic delivery of calcium-permeable AMPARs which contribute to additional calcium signaling post-injury. We have found that both synaptic and extrasynaptic NMDAR activation are required for their delivery and that the activity of multiple kinases contributes to their resulting aberrant signaling. Inhibiting this new population, even after injury, protects against neuronal loss in multiple models of injury and in multiple brain regions important for memory as well as cognitive ability, both of which are known to be impaired following TBI. Together, our findings provide a novel target for treatment post TBI with the added knowledge of the pathways leading to their presence. With a good understanding of a therapeutic target, the chances of unexpected side effects decrease and the concurrent chances of success increase greatly. |
