Neuroscience/Objectives/Lecture 11

From PhysioWiki

PNS and CNS injury: Degeneration and regeneration

List factors that contribute to the consequence of CNS injury.

• Neurons are post-mitotic; limited postnatal neurogenesis (except hippocampus, olfactory bulb).
• CNS depends upon relays which fail if any of their component neurons are rendered nonfunctional.
• Neurons are vulnerable to injury over a wider surface area than most cells (due to projections).
• Axons are very sensitive to injury since they are incapable of protein synthesis.
• Neuronal somata are very sensitive to hypoxia because of their high metabolic activity.
  • After injury, neurons may respond by releasing toxic neurotransmitters (excitotoxicity).
• Neurons require retrograde transport of neurotrophic factors from their targets. (Neurons deprived of all their targets die.)
• Mechanical and ischemic injury is common.

Describe the responses of an axon in the PNS to axotomy.

Severing of the axon divides it into proximal and distal segments. Continued anterograde and retrograde axonal transport leads to swelling in the neuron, with the proximal segment more swollen than distal. This may be due to anterograde transport being much faster than retrograde. Synaptic transmission fails followed by physical disruption of contact between axon terminal and its postsynaptic target (mediated by glia). Loss of the terminal results in degeneration of the distal segment (Wallerian degeneration), during which the myelin sheath fragments and pulls away. Phagocytic cells invade the degenerating distal segment.

The cell body and nucleus may swell and the endoplasmic reticulum may break down (chromatolysis) and move to the periphery of the cell body. This peripheral displacement of the ER may result in an eccentric nucleus.

Compare the reactions of CNS neurons to axotomy with those of PNS neurons.

PNS:

• Transcription and protein synthesis patterns change; more growth-associated proteins (GAPs) are produced.
• Axon terminal clubs proximal to the injury regress to the first node of Ranvier, then form a growth cone with terminal sprouts which grow very well on Schwann cells (since they produce many neurotrophic factors and laminins—a basal lamina component that is a preferred substrate for axonal navigation).
• Axons can reach their target at a rate of regrowth that approximates the rate of axonal transport (1-2 mm/day).
• Growing axons associate with a band of Bungner, a tube of Schwann cells that helps the regenerating axon reach its target.
• Neuromas (and surrounding connective tissue) may form from axons that fail to associate with a band of Bungner.
• Functional regeneration requires navigation of the axon to its original (or a nearby) target. Thus a crush is better recovered from than a cut.

CNS:

• Axonal swelling at terminus
• Loss of axodendritic and axosomatic synapses
• Wallerian (anterograde) degeneration of distal axonal processes and myelination
• Retrograde degeneration of proximal axonal stump
• Growth cone-like structures form at axonal terminals, but they're not maintained
• Regenerative attempts are abortive

Compare and contrast the response of central glial cells (astrocytes and oligodendrocytes) and peripheral glia (Schwann cells) to traumatic injury.

• Astrocytes produce glial scar
• Schwann cells proliferate in response and ensheath synaptic terminals
• Schwann cells produce neurotrophic factors

Describe known factors that contribute the lack of functional regeneration in the CNS.

• Absent or reduced GAP expression
• Absence of Schwann cell-derived neurotrphic factors
• Presence of glial scar produced by hypertrophic astrocytes
• Presence of myelin-associated inhibitors of neurite growth (e.g. Nogo, MAG, OMgP)
• Presence of other inhibitory signals (e.g. NG2)

Describe experimental strategies to promote CNS regeneration.

The main idea is that rho kinase inhibits regeneration in the CNS at the cellular level. Its regulation:

• Nogo, MAG, and OMgp increase rho kinase activity
  • Anti-Nogo antibody promotes axonal regeneration
• cAMP decreases rho kinase activity and stimulates growth programs; therefore cAMP facilitates regeneration
  • Neurotrophic factors (e.g. from Schwann cells) enhance cAMP levels
  • PDE inhibitors enhance cAMP levels

Other ways to promote CNS regeneration:

• Implant more permissive environment (e.g. embryonic tissue, peripheral nerve grafts, olfactory ensheathing cells—similar to Schwann cells and oligodendrocytes)
• Combinations of the above