Journal Article

Schwann cell p75<sup>NTR</sup> prevents spontaneous sensory reinnervation of the adult spinal cord

Angela L. M. Scott and Matt S. Ramer

in Brain

Published on behalf of The Guarantors of Brain

Volume 133, issue 2, pages 421-432
Published in print February 2010 | ISSN: 0006-8950
Published online December 2009 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awp316
Schwann cell p75NTR prevents spontaneous sensory reinnervation of the adult spinal cord

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Schwann cells are attractive candidates for repair of the injured spinal cord. Transplanted Schwann cells are permissive to regeneration, but their ability to promote regeneration into distal spinal cord remains weak despite their production of growth-promoting neurotrophins. Schwann cell activation such as that which accompanies peripheral nerve injury results in massive upregulation of the p75NTR pan-neurotrophin-receptor. Here we test the hypothesis that this p75NTR upregulation following dorsal root injury limits availability of endogenous neurotrophin to axons and restricts regeneration of injured axons into the spinal cord. We injured dorsal roots (fourth cervical to second thoracic) in mice lacking the neurotrophin-binding domain of p75NTR and in wild-type littermates. Axonal regeneration was assessed by selective tracing of neurotrophin-responsive and non-responsive dorsal root ganglion neurons. Functional reinnervation of the spinal cord was assessed in behavioural experiments and via Fos immunohistochemistry following formalin injection into the forepaw. We also measured levels of nerve growth factor and neurotrophin-3 following nerve injury in knockout and wild-type mice, and used Trk-Fc receptor chimeras to block nerve growth factor and neurotrophin-3 signalling in dorsal root ganglion/Schwann cell co-cultures and following dorsal root injury in vivo. The roles of neuronal and glial p75NTR were assessed in transplant experiments in vivo and in co-cultures. We found that nerve growth factor and neurotrophin-3-responsive axons regenerated into the spinal cord of p75NTR knockout mice where they made functional connections with dorsal horn neurons. Despite equivalent levels of nerve growth factor and neurotrophin-3 in wild-type and knockout mice, successful regeneration in knockouts was neurotrophin-dependent. Transplantation of p75−/− neurons into a wild-type environment, p75−/− peripheral nerve grafts into the injured p75+/+ spinal cord, and dissociated sensory neuron/Schwann cell co-cultures showed that the absence of p75NTR from glia, not from neurons, promotes regeneration. These findings indicate that Schwann cell p75NTR restricts neurotrophin availability to the extent that it prevents spontaneous sensory axon regeneration into the spinal cord. The implication is that inactivating p75NTR in Schwann (or olfactory ensheathing) cells may enable axons to grow beyond transplants, improving the outcome of spinal cord injury.

Keywords: nerve growth factor; neurotrophin-3; transplantation; spinal cord injury; glial scar

Journal Article.  7122 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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