The effect of the Val66Met BDNF polymorphism on axon regeneration after peripheral nerve injury Restricted; Files & ToC

McGregor, Claire (Fall 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/np193b07w?locale=en
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Abstract

Although peripheral nerves can spontaneously regenerate after injury, outcome is generally very poor. Activity-dependent treatments to enhance peripheral nerve regeneration after injury have shown great promise, and clinical trials implementing them have begun. Success of these treatments requires activity-dependent release of brain derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP) in the BDNF gene known as Val66Met found in nearly one third of the human population results in defective activity-dependent BDNF secretion and could impact the effectiveness of these therapies. We used a mouse model of this SNP to test the efficacy of treadmill exercise in enhancing axon regeneration in animals both heterozygous (V/M) and homozygous (M/M) for the SNP. Axon regeneration was studied four weeks after complete transection and repair of the sciatic nerve, using both electrophysiological and histological outcome measures. Regeneration was enhanced significantly without treatment in V/M mice, compared to wild type (V/V) controls. Unlike V/V mice, treatment of both V/M and M/M mice with treadmill exercise did not result in enhanced regeneration. These results were recapitulated in vitro using dissociated neurons containing the light-sensitive cation channel, channelrhodopsin. Three days after plating, neurites of neurons from V/M and M/M mice were longer than those of V/V neurons. In neurons from V/V mice, but not those from V/M or M/M animals, longer neurites were found after optical stimulation. Taken together, Met carriers possess an intrinsically greater capacity to regenerate axons in peripheral nerves, but this cannot be enhanced further by activity-dependent treatments. This enhanced axon regeneration can be blocked by application of a trkB antagonist, ANA-12. In culture, application of ANA-12 to adult dorsal root ganglion (DRG) neurons blocks enhanced neurite outgrowth in cells from M/M mice. Application of the fusion protein trkB-Fc which sequesters trkB ligands also results in decreased neurite outgrowth in all genotypes. Inhibiting the pan-neurotrophin receptor, p75NTR, resulted in a modest improvement in V/V axon regeneration, and no effect in Met-carriers. Thus, the enhanced axon regeneration in Met-carriers is trkB-dependent.

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