Traumatic brain injury (TBI) is a devastating worldwide disorder, and is believed to become the third most prevalent health concern contributing to patient mortality by 2020. Trauma to the human brain is an extremely difficult problem that arises from numerous factors including; brain complexity, TBI diversity, numerous cellular targets, and the progressive nature of the injury. Our ability to model TBI in animals is critical for developing therapeutic strategies to minimize damage and/or promote recovery. One common feature of TBI, ranging from concussive to penetrating injuries, is diffuse and progressive synaptic damage that ultimately leads to functional losses. Our studies will model synaptic damage in the absence of neuron losses in the hippocampus to examine mechanisms of action that underlie progressive synaptic damage. We hypothesize that the phasic release of the co-transmitter D-serine from hippocampal glutaminergic neurons plays an important role in regulating synaptic function; however, following injury D-serine is suppressed in neurons but up regulated in astrocytes. Increased tonic release of astrocytic D-serine leads to sub-lethal excititoxic synaptic damage over the first week post-injury. We have also found that enhanced astrocytic D-serine levels are regulated by neuronal-astrocyte communication in the tripartite synapse. Specifically, we hypothesize that neuronal ephrinB3 communicates with astrocytic EphB3 and EphA4 to regulate D-serine production and release. Following TBI, increased levels of Eph signaling in reactive astrocytes results in excessive release of D-serine. Our studies take a comprehensive approach to address our hypotheses using cutting edge techniques and cell specific knockout and knockin mice to investigate the mechanisms that regulate D-serine mediated synaptic function and dysfunction.
The studies described in this proposal will examine the role of D-serine and Eph receptors in regulating synaptic stability and function in the tripartite synapse following traumatic brain injury using novel mouse CCI injury models, cutting edge techniques.
|Perez, Enmanuel J; Tapanes, Stephen A; Loris, Zachary B et al. (2017) Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury. J Clin Invest 127:3114-3125|
|Perez, Enmanuel J; Cepero, Maria L; Perez, Sebastian U et al. (2016) EphB3 signaling propagates synaptic dysfunction in the traumatic injured brain. Neurobiol Dis 94:73-84|