Cooperative Roles of BDNF Expression in Neurons and Schwann Cells Are Modulated by Exercise to Facilitate Nerve Regeneration

Abstract

After peripheral nerve injury, neurotrophins play a key role in the regeneration of damaged axons which can be augmented by exercise, although the distinct roles played by neurons and Schwann cells are unclear. In this study, we evaluated the requirement for the neurotrophin, brain derived neurotrophic factor (BDNF), in neurons and Schwann cells, for the regeneration of peripheral axons after injury. Common fibular or tibial nerves in thy-1-YFP-H mice were cut bilaterally and repaired using a graft of the same nerve from transgenic mice lacking BDNF in Schwann cells (BDNF-/-) or wild-type mice (WT). Two weeks post-repair, axonal regeneration into BDNF-/- grafts were markedly less than WT grafts, emphasizing the importance of Schwann cell BDNF. Nerve regeneration was enhanced by treadmill training post-transection, regardless of the BDNF content of the nerve graft. We further tested the hypothesis that training-induced increases in BDNF in neurons allow regenerating axons to overcome a lack of BDNF expression in cells in the pathway through which they regenerate. Nerves in mice lacking BDNF in YFP+ neurons (SLICK) were cut and repaired with BDNF-/- and WT nerves. SLICK axons lacking BDNF did not regenerate into grafts lacking Schwann cell BDNF. Treadmill training could not rescue the regeneration into BDNF-/- grafts if the neurons also lacked BDNF. Both Schwann cell- and neuron-derived BDNF are thus important for axon regeneration in cut peripheral nerves.

Small-molecule trkB agonists promote axon regeneration in cut peripheral nerves

“…The slowness and incompleteness of axon regeneration is often blamed for these poor functional outcomes (28). In considering the cell biology of axon regeneration, BDNF has emerged as an important molecule that promotes the elongation of regenerating axons, and some methods have been developed to stimulate axon regeneration that rely on the increased production of BDNF and/or its receptor, trkB (9,29,30). However, the potential for treatments of injured nerves with recombinant human BDNF is limited because it is a large molecule that will not cross the blood-brain or bloodnerve barriers well, because its biological half-life is short and because the high doses that might be required would increase the likelihood of toxicity or untoward side effects.…”

“…In this manner they would mimic the effects of endogenous BDNF released by transformed Schwann cells in the pathway used by regenerating axons (8,9). However, other possible mechanisms might exist.…”

“…Cut peripheral nerves were repaired either with grafts from strain-matched WT mice, in which transformed Schwann cells in the grafts are expected to produce normal amounts of BDNF, or from mice in which the gene for BDNF is knocked out selectively in Schwann cells (CNTF-Cre:: (9). Both of these groups were considered controls, because neither was treated with either 7,8 DHF or deoxygedunin.…”

“…In the pathway, it is produced by transformed Schwann cells and stimulates neurite elongation by binding to tropomyosin receptor kinase B (trkB) receptors on the regenerating axons (8,9). Axon regeneration in cut nerves is severely compromised if the availability of BDNF to regenerating axons is reduced, such as by treatments with function-blocking antibodies (10) or by genetic manipulation of BDNF expression in Schwann cells (9). Local treatment of repaired nerves with recombinant human BDNF (rhBDNF) promotes enhanced early regeneration in mice (9,11).…”

“…Axon regeneration in cut nerves is severely compromised if the availability of BDNF to regenerating axons is reduced, such as by treatments with function-blocking antibodies (10) or by genetic manipulation of BDNF expression in Schwann cells (9). Local treatment of repaired nerves with recombinant human BDNF (rhBDNF) promotes enhanced early regeneration in mice (9,11).…”