Growth Differentiation Factor 5 Improves Neurogenesis and Functional Recovery in Adult Mouse Hippocampus Following Traumatic Brain Injury

Hongjie Wu, Jing Li, Dongxiao Xu, Qiansheng Zhang, Tao Cui

The aim of this study was to investigate the therapeutic effect of growth differentiation factor 5 (GDF-5) on traumatic brain injury (TBI) in mice. We utilized a controlled cortical impact to establish a mouse TBI model, and then stereotaxically administered 25 or 100 ng GDF-5 into the bilateral hippocampal dentate gyrus (DG) of each of the animals. Seven days after the injury, some of the animals were sacrificed for immunohistochemical and immunofluorescence examination of 5-bromo-2'-deoxyuridine (BrdU), Sox-2, doublecortin (DCX) and phosphorylated cAMP response element binding protein (p-CREB). Dendrite quantification was also performed using DCX positive cells. Activation of newborn neurons was assessed 35 days after the injury. The remaining animals were subjected to open field, Y maze and contextual fear conditioning tests 2 months after TBI. As a result, we found that post-injury stereotaxical administration of GDF-5 can improve neural stem cell proliferation and differentiation in the DG of the hippocampus, evidenced by the increase in BrdU, Sox-2, and DCX-labeled cells, as well as the improvement in dendrite arborization and newborn neuron activation in response to GDF-5 treatment. Mechanistically, these effects of GDF-5 may be mediated by the CREB pathway, manifested by the recovery of TBI-induced dephosphorylation of CREB upon GDF-5 administration. Behavioral tests further verified the effects of GDF-5 on improving cognitive and behavioral dysfunction after TBI. Collectively, these results reveal that direct injection of GDF-5 into the hippocampus can stimulate neurogenesis and improve functional recovery in a mouse TBI model, indicating the potential therapeutic effects of GDF-5 on TBI.