Mapping synaptic change following mild traumatic brain injury

Centre for Clinical Brain Sciences, University of Edinburgh

Mild traumatic brain injury (mTBI) is a major public health problem with an estimated annual incidence of 300 per 100 000 (1). Patients can go on to suffer from significant post-concussional symptoms and human imaging studies have demonstrated post-injury white matter changes (2). Comparatively little is known about the effect of mTBI at the level of the synapse. There is preclinical evidence that trauma induces reduction in synaptic density (3). However, previous studies have been limited to specific brain sub-regions or whole brain homogenates.

Using the lateral fluid percussion model, we aimed to investigate the impact of a focal traumatic injury on synapses through two synaptic proteins (PSD-95 and SAP-102). Existing literature has shown that a percussion injury leads to axonal pathology and inflammatory changes (4). Our initial study found that a mild (1-1.3 atm) injury led to significant elevations in corpus callosal APP expression and increased inflammatory cells (Iba-1 and GFAP) in the cortex and hippocampus at 24 hours post-injury. Using a double knock-in fluorescent mouse model, we then mapped trauma-induced synaptic changes. A previous study found a delayed decrease in PSD-95 expression at 7 days following a controlled cortical impact in mice (5). In our study, there were limited changes in both proteins between injury and sham mice at 7 days however, changes emerged in the cortex, hippocampus and striatum at 28 days. Differing patterns of change were seen between PSD-95 and SAP102. 

Our data provides a comprehensive temporospatial analysis of synaptopathy following a mild fluid percussion injury. It highlights a delayed reduction in the studied synaptic proteins with differential changes indicating differing synaptic subpopulation changes.

References

1. Cassidy JD, Carroll LJ, Peloso PM, Borg J, von Holst H, Holm L, et al. Incidence, risk factors and prevention of mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med [Internet]. 2004 Feb [cited 2017 Mar 3];(43 Suppl):28–60.
2. E Khong, N Odenwald, E Hashim, and Michael D. Cusimano. Diffusion Tensor Imaging Findings in Post-Concussion Syndrome Patients after Mild Traumatic Brain Injury: A Systematic Review. Front Neurol. 2016; 7: 15
3. Gao X, Deng P, Xu ZC, Chen J: Moderate traumatic brain injury causes acute dendritic and synaptic degeneration in the hippocampal dentate gyrus. PLoS One 6(9):e24566, 2011. Doi: 10.1371/journal.pone.0024566.
4. Carbonell WS, Grady MS: Regional and temporal characterization of neuronal, glial, and axonal response after traumatic brain injury in the mouse. Acta Neuropathol 98(4):396–406, 1999. Doi: 10.1007/s004010051100.
5. Wakade C, Sukumari-Ramesh S, Laird MD, Dhandapani KM, Vender JR: Delayed reduction in hippocampal postsynaptic density protein-95 expression temporally correlates with cognitive dysfunction following controlled cortical impact in mice. J Neurosurg 113(6):1195–201, 2010.

Funded by: the Wellcome Trust Scottish Translational Medicine and Therapeutics Initiative

* entered into the PhD student poster competition