Treatment with the Neurotrophic Protein S100B Increases Synaptogenesis after Traumatic Brain Injury

Release of neurotrophic and growth factors such as S100 calcium-binding protein B (S100B) yields an endogenous repair mechanism following traumatic brain injury (TBI). Although nanomolar S100B concentrations enhance hippocampal progenitor cell proliferation, neuronal differentiation, and cognitive recovery, micromolar concentrations may foster inflammatory effects counteracting neuroplasticity. The purpose of the present study was to investigate the effect of S100B on synaptogenesis and microglial activation following experimental TBI. Male Sprague-Dawley rats (n = 40) were subjected to lateral fluid percussion or sham injury, and S100B (50 ng/h) or phosphate buffered saline (PBS) was infused into the lateral ventricle for 7 days using osmotic micropumps. The animals were euthanized on day 5 or, 5 weeks post-injury, and 5 μm sections, 100 μm apart (bregma -3.3 to -5.6mm) were analyzed histologically. Cell proliferation was assessed injecting the mitotic marker Bromodeoxyuridine (BrdU) on day 2. S100B enhanced significantly the synaptophysin (SYN) expression and microglial activation (ectodysplasin [ED1]) in the hippocampus in TBI and uninjured sham animals. The glial activation (glial fibrillary acidic protein [GFAP], S100B immunoreactive cells), axonal injury (APP) and cell death (terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) were not altered. Triple-labelling with BrdU, NeuN, and SYN confirmed a significant participation of S100B in hippocampal synaptogenesis in TBI and uninjured sham animals. Our results demonstrate that S100B augments hippocampal neuro- and synaptogenesis in TBI and uninjured sham animals, thereby improving cognitive function as demonstrated earlier. The S100B-induced microglial activation does not counteract this effect within the first 5weeks. Further studies are required to elucidate respective cellular signaling mechanisms and possible long-term effects.