LETTER TO THE EDITOR Reply: Is inhibition of axonal regeneration by astrocytes, in the dorsal part of the spinal cord, regulated by p75 receptor?

The p75 neurotrophin receptor is a binding or signalling partner for a long list of receptors and ligands. In neurons, p75 neurotrophin receptor expression regulates the binding affinity between Trk receptors and growth-promoting neurotrophins, as well as their binding specificity (Roux and Barker, 2002). Neuronal p75 neurotrophin receptor also transduces growth inhibition conferred by myelin-derived proteins (McGee and Strittmatter, 2003). These cis interactions are much better understood than those occurring in trans, which may be equally important where glial cells, such as Schwann cells in peripheral nerves, express p75 neurotrophin receptor at high levels. A hypothesized trans role for Schwann cell p75 neurotrophin receptor in peripheral nerve regeneration involves its ‘presentation’ of neurotrophins (themselves produced by Schwann cells) to regenerating Trk-expressing axons (Johnson et al., 1988). In our recent paper, we showed that Schwann cell p75 neurotrophin receptor, rather than presenting neurotrophins to axons, actually reduces their availability: in p75 neurotrophin receptor knockout mice, reactive Schwann cells in injured dorsal roots prompted neurotrophin-dependent axonal regeneration into the spinal cord (Scott and Ramer, 2010). Dr Yuan’s question of whether other glial cell types, astrocytes in particular, become more permissive to growth in the absence of p75 neurotrophin receptor is an interesting one, and he cites studies that report increased expression of p75 neurotrophin receptor in reactive, proliferating astrocytes in the brain. To our knowledge, this is not the case for spinal astrocytes, at least at the detection levels afforded by immunohistochemistry: at the peripheral nervous system–central nervous system transition zone and deeper within the spinal cord, astrocytes are conspicuously p75 neurotrophin receptor-negative, as illustrated in Fig. 1A of our paper (Scott and Ramer, 2010). Indeed, p75 neurotrophin receptor immunolabelling is often used to differentiate spinally grafted Schwann cells or olfactory ensheathing glial cells from endogenous spinal glia (Ramer et al., 2004). Furthermore, injured sensory axons do not penetrate the astrocytic scar that forms at the site of a spinal cord injury in p75 neurotrophin receptor knockout mice (Song et al., 2004), indicating that spinal p75 neurotrophin receptor-negative astrocytes remain inhibitory. There also appears to be no difference in the level of reactivity of astrocytes in the injured spinal cord of the two genotypes, as indicated with the immunohistological marker glial acid fibrillary protein (personal communication). It is, however, becoming clear that brainand spinal cord-derived astrocytes are intrinsically different (Hewett, 2009), and it will be interesting to determine whether or not astroglial p75 neurotrophin receptor in the brain plays a similar role to that of peripheral Schwann cells in restricting regeneration. Dr Yuan also points out that since p75 neurotrophin receptor participates in myelination, simple p75 neurotrophin receptor antagonism may fail as a potential therapy if regenerated axons end up hypoor un-myelinated. Our own studies investigated recovery of thermosensation and nocioception, which are subserved by unmyelinated sensory axons; and so we cannot yet say whether or not behavioural responses dependent upon low-threshold, fast-conducting mechanoreceptors and proprioceptors also recover. However, studies on motor axon regeneration, the efficacy of which also depends on myelination, report improved function (Ferri et al., 1998; Boyd and Gordon, 2001). Should the dependence of myelination on p75 neurotrophin receptor turn out to impede functional recovery following spinal transplantation of p75 neurotrophin receptor negative Schwann cells, then our attention should turn to blocking doi:10.1093/brain/awq020 Brain 2010: 133; 1–2 | e145