Neuroscience Online (i,9,4)

Neurons of the CNS Have Very Limited Capacity To Regenerate

Damage to CNS neurons is often irreversible. Why are CNS neurons different than peripheral neurons in this regard? In the adult brain important ECM molecules like laminin and fibronectin are no longer expressed and thus important adhesion molecules are absent from the regenerating environment. In addition, oligodendroglia (the myelinating cells of the CNS) express growth inhibitory molecules in the adult that block axon regrowth.

As discussed above, the environment and properties of peripheral nerves are much more supportive of the regeneration process. For example, Schwann Cells secrete NGF, ECM and other adhesive molecules that are critical for neuronal survival and axon regeneration. In addition, Schwann cells do not express molecules that inhibit axon growth like oligodendroglia in the CNS. The use of peripheral nerve grafts to promote regeneration of damaged nerves in the CNS is one possible way to overcome the limited regeneration potential of CNS neurons.

For example, following transection of the optic nerve, if a section of peripheral nerve is attached to the cut end of the optic nerve and its other end is inserted into superior colliculus, then regeneration of the optic nerve can occur. Evidence supporting the functional regeneration of the cut optic nerves includes:

Retinal ganglion axons regenerated and reinnervated the superior colliculus.
New synapses are formed which last for at least one year.
These new synapses are functional; if retinal neurons are activated by light, then postsynaptic neurons in the colliculus respond (they also respond to direct electrical stimulation of retinal neurons).
Experimental subjects with PNS nerve grafts have partially restored light avoidance behavior.
Administration of growth factors during nerve grafts can enhance regeneration.

NGF also appears to play an important role in the survival of cholinergic neurons of the basal forebrain where neurons degenerate in Alzheimer's disease.

Figure 9.40

General Relationships between Pre- and Postsynaptic Neurons During Injury and Regeneration. Following damage to an axon by cutting, a sequence of changes occurs during degeneration. Under certain conditions, both retrograde and anterograde transneuronal degeneration can occur.

Cutting an axon divides it into proximal and distal segments
Immediately after injury, axons begin to seal off, however, Ca²⁺ enters damaged axonal elements and activates Ca²⁺-dependent proteases
Rapid failure of synaptic transmission occurs within hours (depending on where the axon is cut relative to the distal-proximal axis; metabolic and protein synthetic machinery remains in the cell body)
Within days presynaptic terminals begin to degenerate and in about 1 week invading glia disrupt and phagocytose synaptic contacts
The distal segment degenerates slowly and may take up to 1 month; the loss of distal segments is called Wallerian degeneration
There are also major changes that occur in the neuronal cell body during degeneration; a few days after axotomy, the process of chromatolysis starts in the soma:
1. RER (rough endoplasmic reticulum) breaks down and moves to periphery of the cell body (or soma).
2. There is an increase in free polyribosomes, mRNA transcription and protein synthesis (the injured neuron's response to injury is to increase its metabolic rebuilding).
3. A damaged neuron's success in regeneration is linked to its ability to find an appropriate target to reinnervate; failure to contact a target usually results in cell death.

If the injured neuron survives damage (and this often depends on the appropriate trophic factors being present), the process of reinnervation begins:

The axon's proximal segment forms sprouts and the process of regrowth begins.
Axonal sprouts migrate into the conduit formed by the residual endoneural sheath that surrounded the previous axon.
Axon sprouts migrate to find a target; if a suitable target is found, the neuron survives; if not, the neuron dies.

Cellular damage is not restricted to injured neurons; degeneration is often transneuronal or transsynaptic. In the visual pathway, damage of retinal ganglion neurons often results in degeneration of downstream target neurons in the lateral geniculate and even to neurons in the visual cortex. This is called transsynaptic anterograde degeneration. This process can also happen in the reverse direction (i.e., damage to visual cortex neurons can result in degeneration of geniculate and then retinal neurons), and is called transsynaptic retrograde degeneration.

Traumatic injury to neurons is often irreversable. However, in those instances in which neurons do regenerate following injury, the mechanisms that contribute to regeneration are similar to those events that contribute to axonal growth and synapse formation during development.

During normal development synapse formation is a gradual process that results in one muscle fiber becoming innervated by one motor axon. Following axotomy, the postsynaptic structures called synaptic gutters remain on the surface of the muscle fiber.

During reinnervation, the nerve forms new synaptic contacts at the old synaptic gutters: the one-to-one relationship between nerve and muscle fiber is maintained.

Figure 9.41

New Frontiers - Tissue/Cell Transplants

A large number of crippling neurological conditions result from the loss of certain cell populations from the nervous system through disease or injury, and these cells are not intrinsically replaced. Replacement of depleted cell populations by transplantation may be of functional benefit in many such diseases. A diverse range of cell populations is vulnerable, and the loss of specific populations results in circumscribed deficits in different conditions. This diversity presents a considerable challenge if cell replacement therapy is to become widely applicable in the clinical domain, because each condition has specific requirements for the phenotype, developmental stage, and number of cells required.

New discoveries have made inroads in the use of immortalized cell lines to replace or supplement the decreased or lost functions of damaged nervous system tissues. There have also been limited advances in the area of transplantation using fetal tissues (however, this approach is ethically controversial). Areas in which these new approaches have been tried include:

the synthesis and secretion of catecholamines in patients with Parkinson's disease
the synthesis and secretion of growth/trophic factors (e.g., NGF) in patients with Alzheimer's disease
the synthesis and secretion of ECM and adhesion molecules to promote regeneration in patients with damaged CNS or PNS tissues

These approaches are technically complicated at both cellular and molecular levels. One of the problems encountered is that although tissue or cell transplants seem to have positive short-term benefits, their long-term effects have been limited.

Stem Cells

An ideal cell for universal application in cell replacement therapy would possess several key properties: it would be highly proliferative, allowing the ex vivo production of large numbers of cells from minimal donor material; it would also remain immature and phenotypically plastic such that it could differentiate into appropriate neural and glial cell types on, or prior to, transplantation. Critically, both proliferation and differentiation would be controllable. Neural stem cells exist not only in the developing mammalian nervous system but also in the adult nervous system of all mammalian organisms, including humans. Neural stem cells can also be derived from more primitive embryonic stem cells. The cells can be expanded, established in continuous cell lines and differentiated into the three classical neuronal phenotypes (neurons, astrocytes, and oligodendrocytes). The mechanisms that regulate endogenous stem cells are poorly understood. Potential uses of stem cells in repair include transplantation to repair missing cells and the activation of endogenous cells to provide "self-repair. " Before the full potential of neural stem cells can be realized, we must understand what controls their proliferation, as well as the various pathways of differentiation available to their daughter cells.

Summary

Postsynaptic targets supply critical neurotrophic factors.
In addition to NGF, several neurotrophic factors have been identified (e.g., BDNF and neurotrophin 3).
Reactions of neurons to injury can vary dramatically; neurons usually survive if functional connections are formed during the regeneration process.
Although regeneration is possible in the PNS, regeneration in the CNS is poor or nonexistent.

Future biomedical research will continue to actively pursue approaches to restore the function of damaged neuronal tissues. The future of understanding important molecules and mechanisms that underlie regeneration lies in basic neurobiological research. Areas to receive attention include:

The identification of new cell-surface and extracellular matrix molecules that promote axon growth and regeneration.
The identification and production of new trophic factors that are essential for cell survival and growth.
The examination of potential use of embryonic stem cells to functionally replace lost neurons.
In addition, tissue transplantation and peripheral nerve grafts will continue to be studied since they represent one of the most viable approaches to CNS regeneration.

Test Your Knowledge

9. All of the following are guidance cues for axonal outgrowth and pathfinding EXCEPT:

A. Cell surface adhesion molecules
B. Directional cues from guidepost cells
C. Pioneer axons
D. Filopodia
E. Extracellular Matrix Molecules

10. Agrin: