Degeneration and Regeneration of the Nervous System

Changes to PNS Axon upon Axotomy (Cut Axon)

distal axon:

Wallerian degeneration (cut end seals, swells with organelles carried by retrograde axoplasmic transport)
Schwann cells multiply and undergo phagocytosis of myelin; macrophages also digest myelin debris
1-2 days: membrane breaks down, influx of Ca⁺⁺ activates proteolysis of vesicles and cytoskeleton
this happens a few mm proximal to cut as well ("dying back")

cell body detects injury – undergoes chromatolysis (changes that prepare for formation of a new axon)

RER breaks up (free ribosomes), cell body swells, nucleus in eccentric location (typical of developing)
synapses withdraw from presynaptic axon so no longer threshold activation of the nerve
metabolism shifts (makes tubulin and actin, not neurotransmitter and neurofilaments)
extent of chromatolysis depends on neuron type (alpha motor > thalamic), cut proximity (farther > closer), age (adult > child), environment (transneuronal degeneration: pre- or postsynaptic can degenerate too)

Regeneration

Success of Regeneration

determined by environment—must be conducive to regrowth and reconnection (different in CNS vs. PNS)
growth cone—motile organ at distal tip of axon that probes environment

interacts with adhesion and signalling molecules such as laminin, NCAM, NgCAM/L1, etc.
allow growth cone to adhere, transduce signals to cytoskel (directly alter motility of growth cone)

in the PNS, regeneration is usually successful

distal Schwann cells proliferate and express adhesion molecules (NCAM, N-cadherin, NgCAM), receptors (e.g., for P75 low affinity growth factor), and secrete growth promoting molecules
can follow same endoneural tube (substrata contains original molecules)—so crush better than cut
grow until reach targets, then synapse where a synapse has previously occurred (agrin at old synapse)

not always at same synapse as before – innervate adjacent muscle fibers rather than in native checkerboard (fiber-type clumping)
if prevent binding to synapse: continue to elongate, producing tangled mass of axons with swollen tips (neuroma)

when remyelinated, myelin is thinner with shorter internodes, so conduction is not as good
since fascicles rearrange, growth cone can enter wrong tube if proximal (innervate wrong muscles)

in the CNS, regeneration is often less successful

chromatolysis does occur, but regeneration is very poor (grow well only if environment approximates PNS)
five factors make the CNS an unfavorable environment:

(1) oligodendrocytes do not divide, and myelin remains (myelin has inhibitory molecules)

(2) oligodendrocytes have inhibitory molecules (which can be stopped by antibodies)

(5) if blood-brain barrier is compromised, macrophages and proteoglycans inhibit axon growth

So How Can CNS Axonal Regeneration be Facilitated (experimentally or clinically)? – Four Strategies