Traumatic brain injury (TBI) results in a number of acute pathological alterations including the extracellular release of glutamate3-5. This acute transmitter release is thought to play a significant role in early neuronal cell death6,7. Although progressive synaptic damage also plays a significant role in functional loss8, and unfortunately our understanding of transmitter regulation in the days and weeks after TBI is limited. Glial cells in particular astrocytes, play an important role in maintaining synaptic integrity and function aftr injury by regulating transmitter levels in the synaptic cleft9-12. In addition, a family of recepto tyrosine kinases, Eph receptors, and their cognate ligands, ephrins, regulates synaptic function and formation as well as transmitter synthesis and release from astrocytes13-17. We hypothesize that neurons communicate with astrocytes through ephrinB3-EphB3 signaling to regulate glial transmitter levels in the synapse, and through enhancement of EphB3 signaling we can improve synaptic stability and function after TBI. In this study, we will examine how varying transmitter levels through genetic manipulation of transmitter enzymes (i.e. serine racemase) and ephrinB3-EphB3 signaling in astrocytes and/or neurons affects synaptic stability and function after TBI. We will take a comprehensive approach and make use of cutting-edge techniques to measure synaptic transmission, transmitter release, biochemical alterations in protein expression, and learning and memory behavior using gain-of-function and loss-of-function mouse models.
Greater than 2 % of Americans are living with long-term disabilities as a consequence of traumatic brain injuries (TBIs)1, and direct and indirect costs of TBI are estimated to be greater than $70 billion a year2. However, there are currently no therapeutic strategies available for the treatment/prevention of these long-term consequences. Understanding long-term influences of transmitter levels and glial function on synaptic stability and plasticity within the injured brain represents good therapeutic targets for boosting the brains re-innervation capacities and preventing long-term cognitive dysfunction.