Box DWhy Aren't We More Like Fish and Frogs?

The central nervous system of adult mammals, including humans, recovers only poorly from injury. As indicated in the text, once severed, major axon tracts (such as those in the spinal cord) never regenerate. The devastating consequences of these injuries—e.g., loss of movement and the inability to control basic bodily functions—has led many neuroscientists to seek ways of restoring the connections of severed axons. There is no a priori reason for this biological failure, since “lower” vertebrates—e.g., lampreys, fish, and frogs—can regenerate a severed spinal cord or optic nerve. Even in mammals, the inability to regenerate axonal tracts is a special failing of the central nervous system; peripheral nerves can and do regenerate in adult animals, including humans. Why, then, not the central nervous system?

At least a part of the answer to this puzzle apparently lies in the molecular cues that promote and inhibit axon outgrowth. In mammalian peripheral nerves, axons are surrounded by a basement membrane (a proteinaceous extracellular layer composed of collagens, glycoproteins, and proteoglycans) secreted in part by Schwann cells, the glial cells associated with peripheral axons. After a peripheral nerve is crushed, the axons within it degenerate; the basement membrane around each axon, however, persists for months. One of the major components of the basement membrane is laminin, which (along with other growth-promoting molecules in the basement membrane) forms a hospitable environment for regenerating growth cones. The surrounding Schwann cells also react by releasing neurotrophic factors, which further promote axon elongation (see text). This peripheral environment is so favorable to regrowth that even neurons from the central nervous system can be induced to extend into transplanted segments of peripheral nerve. Albert Aguayo and his colleagues at the Montreal General Hospital found that grafts derived from peripheral nerves can act as “bridges” for central neurons (in this case, retinal ganglion cells), allowing them to grow for over a centimeter (figure A); they even form a few functional synapses in their target tissues (figure B).

These several observations suggest that the failure of central neurons to regenerate is not due to an intrinsic inability to sprout new axons, but rather to something in the local environment that prevents growth cones from extending. This impediment could be the absence of growth-promoting factors—such as the neurotrophins—or the presence of molecules that actively prevent axon outgrowth. Studies by Martin Schwab and his colleagues point to the latter possibility. Schwab found that central nervous system myelin contains an inhibitory component that causes growth cone collapse in vitro and prevents axon growth in vivo. This component, recognized by a monoclonal antibody called IN-1, is found in the myelinated portions of the central nervous system but is absent from peripheral nerves. IN-1 also recognizes molecules in the optic nerve and spinal cord of mammals, but is missing in the same sites in fish, which do regenerate these central tracts. Nogo-A, the primary antigen recognized by the IN-1 antibody, is secreted by oligodendrocytes, but not by Schwann cells in the peripheral nervous system. Most dramatically, the IN-1 antibody increases the extent of spinal cord regeneration when provided at the site of injury in rats with spinal cord damage. All this implies that the human central nervous system differs from that of many “lower” vertebrates in that humans and other mammals present an unfavorable molecular environment for regrowth after injury. Why this state of affairs occurs is not known. One speculation is that the extraordinary amount of information stored in mammalian brains puts a premium on a stable pattern of adult connectivity.

At present there is only one modestly helpful treatment for CNS injuries such as spinal cord transection. High doses of a steroid, methylprednisolone, immediately after the injury prevents some of the secondary damage to neurons resulting from the initial trauma. Although it may never be possible to fully restore function after such injuries, enhancing axon regeneration, blocking inhibitory molecules and providing additional trophic support to surviving neurons could in principle allow sufficient recovery of motor control to give afflicted individuals a better quality of life than they now enjoy. The best “treatment,” however, is to prevent such injuries from occurring, since there is now very little that can be done after the fact.

Image ch25fbd1.jpg
Image ch25fbd2.jpg

Implantation of a section of peripheral nerve into the central nervous system facilitates the extension of central axons. (A) Mammalian retinal ganglion neurons, which do not normally regenerate following a crush injury, will grow for many millimeters into a graft derived from the sciatic nerve. (B) If the distal end of the graft is inserted into a normal target of retinal ganglion cells, such as the superior colliculus, a few regenerating axons invade the target and form functional synapses, as shown in this electron micrograph (arrowheads). The dark material is an intracellularly transported label that identifies particular synaptic terminals as originating from a regenerated retinal axon. (A after So and Aguayo, 1985; B from Bray et al., 1991.)

References

  1. Bray G. M. , Villegas-Perez M. P. , Vidal-Sanz M. , Aguayo A. J. The use of peripheral nerve grafts to enhance neuronal survival, promote growth and permit terminal reconnections in the central nervous system of adult rats. J. Exp. Biol. (1987);132:5–19. [PubMed: 3323406]
  2. Schnell L. , Schwab M. E. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature. (1990);343:269–272. [PubMed: 2300171]
  3. Vidal-Sanz M. , Bray G. M. , Villegas-Perez M. P. , Thanos S. , Aguayo A. J. Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat. J. Neurosci. (1987);7:2894– 2909. [PMC free article: PMC6569122] [PubMed: 3625278]

From: Recovery from Neural Injury

Cover of Neuroscience
Neuroscience. 2nd edition.
Purves D, Augustine GJ, Fitzpatrick D, et al., editors.
Sunderland (MA): Sinauer Associates; 2001.
Copyright © 2001, Sinauer Associates, Inc.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.