Why Axons of Mammalian CNS Exhibit Limited Regeneration

The mammals possess a lot of benefits against other vertebrates, mainly in the areas of cognitive capacity and behavioral flexibility that are unapproachable by fish and amphibians. Yet, quite paradoxically, the latter simple organisms retain an enhanced capability for axonal regeneration in the adult CNS after trauma. In this respect, while an optic nerve can be transected in a frog, it has the capacity to regrow. For example, the result in humans for this type of injury is permanent blindness. Although mammalian CNS axons can elongate considerable distances early in development, there is an abrupt change shortly after birth such that the CNS-white matter becomes an adverse environment for axon growth.

Following injury to an axon, the distal segment degrades because it is separated from the soma of the neuron. The proximal segment's severed tip first tries to regenerate with the formation of growth cones. Unfortunately, in the adult mammalian CNS, this regeneration is ultimately stifled. The situation is different in the PNS; individuals who have received deep cuts that cut peripheral nerves often recover sensation in the affected skin because of the intrinsic regenerative ability of PNS axons.

An important feature distinguishing the mammalian PNS from the CNS is not the neurons themselves. For example, an axon of a dorsal root ganglion cell of the PNS can regenerate in the peripheral nerve but when it reaches the CNS environment, namely the spinal cord's dorsal horn, growth ceases. Conversely, if an alpha motor neuron axon is cut in the peripheral region of an alpha motor neuron from the CNS, the axon can regenerate, but if injured within the CNS, regeneration does not occur. Thus, the basic difference in terminology between CNS / PNS relates to the environments of the two regions.

This hypothesis was tested rigorously in a series of landmark experiments begun in the early 1980s by Albert Aguayo and colleagues at Montreal General Hospital. They found that crushed optic nerve axons could grow over long distances when supplied with a peripheral nerve graft as a growth pathway. However, when these axons reached the CNS target of the graft, their growth stopped again.

|What are the unique properties of peripheral nerves?

The main difference here is the myelinating cells—the CNS has oligodendrocytes, while the PNS contains Schwann cells. Such experiments, carried out by Martin Schwab at the University of Zurich, have shown that CNS neurons grown in tissue culture are capable of growing axons along substrates constructed from Schwann cells, but not along those constructed from CNS oligodendroglia and myelin. This seminal observation led to the pursuit of glial determinants that may restrain axonal elongation and eventually resulted in the isolation of a molecule identified as Nogo in early 2000. Nogo is thought to be released following damage to oligodendroglia.

Later studies demonstrated that antibodies generated against Nogo can overcome its inhibitory influence on growth. Schwab and colleagues conducted experiments where they injected an anti-Nogo antibody known as IN-1 into adult rats after the injury of their spinal cord. This led to axon regeneration of roughly 5% of the axons cut during the injury. While this might not seem like a very impressive result, it was the extent needed to cause substantial functional recovery in the animals used in the experiment. Furthermore, these antibodies have been used to identify the distribution of Nogo in the nervous system. It is synthesized by oligodendroglia in mammals, but it is undetectable in fish, and it is not made by Schwann cells.

A crucial step in the maturation of the mammalian brain is the myelination of the young axons, which dramatically increases the conduction velocity of the action potentials. However, this process is accompanied by a major drawback: it prevents axon growth after injury. For most of the past century, insufficient regeneration of axons in the adult CNS was considered an unfortunate fact of life by neurologists. Nevertheless, our increasing understanding of molecules that activate or block CNS axon growth do encourage hope for the 21st century, and possibly for novel therapies aimed at enhancing axon regeneration within damaged human brains and spinal cords.

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