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The role of p75NTR in axonal regeneration and intraspinal plasticity following spinal deafferentation Scott, Angela Lee

Abstract

Following spinal cord injury (SCI), functional recovery is extremely limited in adult mammals. This lack of recovery is reflective of the failure of axons to regenerate and the incapacity of uninjured neurons to compensate for the lost connections. In animal models of SCI, the administration of neurotrophic factors such as neurotrophins promotes both the regeneration and sprouting of injured and uninjured axons. Neurotrophins elicit these growth-promoting effects through tropomyosin-related kinase (Trk) receptors. However, neurotrophins also interact with a pan neurotrophin receptor, p75NTR. Several functions of the p75NTR receptor have been reported, but its role in neurotrophin-mediated signalling following SCI remains unclear. To determine the role of p75NTR in neurotrophin-mediated axonal regeneration and sprouting within the CNS, I assessed anatomical changes and functional outcomes following spinal deafferentation in mice lacking the neurotrophin-binding domain of p75NTR (p75-/-) and in wild-type littermates (p75+/+). Regeneration of sensory axons was significantly greater in p75-/- mice, and resulted in functional re-connection with dorsal horn neurons. Axonal regeneration in the p75-/- mice was neurotrophin-dependent, and dis-inhibited by the absence of p75NTR expression on glial cells following injury. These findings indicate that glial expression of p75NTR restricts neurotrophin availability to the extent that it prevents spontaneous sensory axon regeneration into the spinal cord. Intraspinal sprouting of uninjured neuronal processes following dorsal root injury was also evaluated in p75+/+ and p75-/- mice. The density of sprouting axons was significantly enhanced by the application of exogenous neurotrophins and dis-inhibited by the absence of p75NTR. Dendritic density was also promoted by exogenous neurotrophin treatment, but was not affected by the absence of p75NTR. Together, these results demonstrate that p75NTR restricts the intraspinal sprouting of neurotrophin-responsive axons, but not dendrites, within the injured spinal cord. Dis-inhibition of dendritic plasticity was, however, correlated to the antagonism of truncated TrkB receptor (TrkBT1) expression. Thus, the neurotrophin receptors p75NTR and TrkBT1 may differentially inhibit intraspinal sprouting of pre- and post-synaptic processes within the spinal cord following injury.

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