Axotomy Upregulates the Anterograde Transport and Expression of Brain-Derived Neurotrophic Factor by Sensory Neurons

Abstract

In addition to the known retrograde transport of neurotrophins, it is now evident that endogenous brain-derived neurotrophic factor (BDNF) is transported in the anterograde direction in peripheral and central neurons. We used a double-ligation procedure that distinguishes between anterograde and retrograde flow to quantify the anterograde transport of endogenous neurotrophins and neuropeptides in the peripheral nervous system before and after axotomy. BDNF accumulation proximal to the ligation (anterograde transport) was twice that distal to the ligation (retrograde direction). Anterograde transport of nerve growth factor and neurotrophin-3 was not evident. Furthermore, BDNF anterograde transport increased 3.5-fold within 24 hr after sciatic nerve injury or dorsal rhizotomy. Anterograde transport of substance P and calcitonin gene-related peptide decreased after peripheral nerve lesion, demonstrating that there was no generalized increase in anterograde transport. To determine the source of the anterogradely transported BDNF, we performed in situ hybridization in a variety of tissues before and after axotomy. Expression of BDNF mRNA in proximal nerve segments did not change with treatment, showing that the increased accumulation of BDNF was not a result of increased local synthesis. BDNF mRNA and protein were expressed by dorsal root ganglion sensory neurons but not by motor neurons. BDNF mRNA expression was increased 1 d after nerve injury, and BDNF protein was also increased twofold to threefold, suggesting that sensory neurons are the major contributing source of the increased BDNF traffic in the sciatic nerve. Our results suggest that increased anterogradely transported BDNF plays a role in the early neuronal response to peripheral nerve injury at sites distal to the cell body.

Long-range signaling within growing neurites mediated by neurotrophin-3

“…The exact nature of the retrograde signal carrier, however, remains controversial (38,39). There are also precedents for the rapid anterograde signaling mediated by neurotrophins (11,26) and anterograde transport of neurotrophins themselves (40,41). In our experiments, NT-3-mediated signal may be transmitted from the site of NT-3 application to the presynaptic terminal through the extracellular medium, by lateral diffusion in the axonal plasmalemma or through the axonal cytoplasm.…”

TRPC4 in Rat Dorsal Root Ganglion Neurons Is Increased after Nerve Injury and Is Necessary for Neurite Outgrowth

“…TRPC5 is present in neuronal cytoplasmic transport vesicles, and its activation is controlled by epidermal growth factor and BDNF through control of rapid vesicular translocation and insertion (30,31). BDNF synthesis and anterograde transport are increased in large diameter DRG neurons within 24 h after sciatic nerve injury (24,25,32,33). Thus, it is likely that TRPC4 activity in growth cones is enhanced by an increased release of growth factors after nerve injury.…”

Anterograde Transport and Secretion of Brain-Derived Neurotrophic Factor along Sensory Axons Promote Schwann Cell Myelination

“…This suggests that target tissues express and secrete neurotrophins, whereby they are internalized by axon terminals and activate signaling pathways in neuronal cell bodies after retrograde transport (Howe and Mobley, 2005;Zweifel et al, 2005). In certain cases, neurotrophins can also be expressed by neurons and act by anterograde transport mechanisms (Zhou and Rush, 1996;Tonra et al, 1998). Double ligation of rat sciatic nerves results in the ac- cumulation of BDNF both proximally and distally to the ligated segment, illustrating both anterograde and retrograde transport, respectively (Zhou and Rush, 1996).…”