Abstract
Synaptic dysfunction and impaired plasticity can have a significant impact on motor, sensory and cognitive functions in traumatic brain injury (TBI) patients. Neuronal death is a predominant underlying cause for synaptic loss in regions of tissue damage. However, synaptic dysfunction can also be present in more distal brain regions where neuronal loss is not observed. To examine synaptic dysfunction within the complex and evolving TBI environment, we utilized a moderate controlled cortical impact (CCI) injury model that leads to hippocampal synaptic damage, and deficits in hippocampal synaptic plasticity and learning without neuronal losses. Proliferation and hypertrophy of astrocytes (i.e. reactive astrocytosis) is a common pathological feature of TBI. However, how reactive astrocytes participate in changes in tripartite synaptic function is not well understood. Therefore, we examined the role of gliotransmission in synaptic function and plasticity following our established mild CCI injury model. Our CCI injury model enabled us to investigate mechanisms of progressive synaptic damage by eliminating serine racemase (SR), an essential enzyme that converts L-serine to D-serine, in cell-specific inducible SR knockout mice (i.e. cSRKO). We show that astrocytic and neuronal D-serine play unique roles in the injured and non-injured CA1 hippocampus, respectively. In non-injured conditions SR is expressed by pyramidal neurons, where D-serine functions to regulate long-term potentiation (LTP). After CCI injury, SR expression switches from neurons to astrocytes, where astrocyte-derived D-serine lead to CCI injury-induced synaptic damage that results in LTP and learning deficits. A family of receptor tyrosine kinases, Eph receptors, and their coganate ligands, ephrins, have been associated with pre-and post-synaptic membranes as well as glial cells in the hippocampus. In particular, EphB3 receptors contribute to regulation of excitatory synaptic numbers, synaptic plasticity and gliotransmission of D-serine; however, the contribution of EphB3 to regulating D-serine levels and synaptic function after TBI is yet to be elucidated. In the CCI injured hippocampus, we found that EphB3-/- mice showed no decrease in synaptic numbers compared to sham controls, and improved synaptic plasticity and learning as compared with wild-type (WT) CCI injured mice. Comparison of key synaptic proteins essential for excitatory synaptic transmission showed no differences between WT and EphB3-/- mice; however, increases in the NMDAR co-agonist D-serine following CCI injury were significantly reduced in the absence of EphB3. Furthermore, rescuing D-serine levels in EphB3-/- mice restored the synaptic deficits observed in WT CCI injured mice. These findings support our previous conclusions, where elevated D-serine levels in the hippocampus may play deleterious roles by destabilizing synapses after TBI, and suggest ephrin-EphB3 signaling regulates these processes.