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Neurotrophins and the neuronal response to axotomy

University of British Columbia

Unlike facial motoneurons (FMNs), which successfully regenerate after axotomy, rubrospinal neurons (RSNs) undergo a marked atrophy in the second week following cervical axotomy. This delayed atrophy is accompanied by a decline in the expression of regeneration associated genes (RAGs), such as GAP-43 and Ta1-tubulin, which are initially elevated after injury. This observation correlates with the growth of only a small percentage of rubrospinal axons into the permissive environment of a peripheral nerve (PN) implanted into the cord at the level of transection. After low thoracic axotomy, there is no increase in RAG expression which also correlates with complete failure of rubrospinal to regenerate into a PN transplant. The overall hypothesis is that these contrasting outcomes are attributed to differences in availability of trophic support between axotomized FMNs and RSNs. Due to their central roles in the nervous system, this thesis focuses on neurotrophins and their receptors. In situ hybridization and reverse transcription-polymerase chain reaction reveal that intact FMNs as well as RSNs express receptor tyrosine kinase(trk) B, a receptor for brain-derived neurotrophic factor (BDNF) and neurotrophin(NT)-4/5, and low level of trkC, a preferred receptor for NT-3, but little trkA. After facial nerve transection, FMNs markedly increase the expression of BDNF and trkB. Whereas this increase is not seen in RSNs after cervical axotomy, supporting the concept that axotomized RSNs receive limited trophic support. These observations lead to the further hypothesis that axotomized RSNs will be responsive to exogenous application of BDNF, NT4/5 or NT-3 based on the trk receptor expression profiles. Application of BDNF or NT-4/5 fully prevents atrophy of RSNs and a decline in the expression of GAP-43 and Ta1-tubulin after cervical injury. Moreover, there is a 3 fold increase in numbers of regenerating RSNs into the PN transplants. Even after thoracic axotomy, BDNF infusion stimulates the expression of GAP-43 and Ta-1 tubulin and overcomes the complete failure of RSNs to regenerate into the PN transplants. This thesis supports the concept that application of an appropriate trophic factor promotes regenerative propensity of injured CNS neurons and provides insights for a development of therapeutic strategies after spinal cord injury.

Thesis/Dissertation

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2009-06-22

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http://hdl.handle.net/2429/9517

Zoology

University of British Columbia

UBCV

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