| Abstract No.: | C-C3110 |
| Country: | Canada |
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| Title: | P75NTR INHIBITS NEUROTROPHIN-MEDIATED REGENERATION AND PLASTICITY FOLLOWING SPINAL DEAFFERENTATION |
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| Authors/Affiliations: | 1 Angela Scott*; 1 Matt Ramer;
1 University of British Columbia, Vancouver, BC, Canada
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| Content: | Following spinal deafferenation, sensory axons fail to spontaneously regenerate into the central nervous system (CNS), and compensatory sprouting of uninjured axons within the spinal cord is limited. Underlying factors that contribute to both the failure of axonal regeneration and the restriction of axonal plasticity include the presence of inhibitory molecules such as myelin-associated inhibitory proteins (MAIPs), and the inadequate supply of neurotropic and neurotrophic support. Since both MAIP and neurotrophin signalling converge on the p75 neurotrophin receptor (p75NTR), we hypothesized that p75NTR plays a central role in the inhibition of axonal regeneration and plasiticity. When active, p75NTR stimulates RhoA, a small GTPase that reduces actin turnover and leads to growth cone collapse. In the CNS, degenerating oligodendrocytes express MAIPs, which activate p75NTR and stimulate RhoA. Neurotrophins, such as nerve growth factor (NGF) and neurotrophin-3 (NT-3), enhance axonal growth via tropomyosin-related tyrosine receptors (Trks), and prevent RhoA activation via p75NTR. In this study, we investigated the role of p75NTR by examining primary afferent axonal regeneration across the dorsal root entry zone (DREZ) and intraspinal plasticity following cervical dorsal root injury in wild-type (p75+/+) and p75NTR knockout mice (p75-/-). In p75+/+ mice, subpopulations of primary afferents regenerated within the PNS up to the CNS boundary of the DREZ, but failed to re-enter the CNS. Conversely, injured primary afferents spontaneously penetrated the DREZ in p75-/- mice, evident at 7 and 28 days post-injury, resulting in the functional re-innnervation of the dorsal horn. Regeneration of several afferent populations was prevented in the p75-/- mice when treated with neurotrophin-antagonists (soluble Trk-Fc). Additionally, intraspinal sprouting of bulbospinal neural populations, as well as, uninjured afferents was greater in the p75-/- mice in comparison to p75+/+ mice. Given these results, we concluded that the antagonism of p75NTR dis-inhibits neurotrophin-mediated axonal regeneration across the PNS:CNS interface and intraspinal plasticity following spinal deafferentation. |
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