Biology Reference
In-Depth Information
visual function. New findings show that a combination of therapies that act synergisti-
cally to activate RGCs
intrinsic growth state enables these cells to regenerate their axons
the full length of the optic nerve, across the optic chiasm, and into the brain, where they
establish synapses in appropriate target zones and restore limited visual responses.
These treatments involve the induction of a limited inflammatory response in the
eye to increase levels of oncomodulin and other growth factors; elevation of intracel-
lular cAMP; and deletion of the pten gene in RGCs. Although these methods cannot be
applied in the clinic, they point to strategies that might be.
'
After injury, neurons of the mature mammalian central nervous system
(CNS) are unable to regenerate damaged axons over appreciable distances.
In addition, undamaged neurons have only a limited ability to form compen-
satory circuits, and there is relatively little replacement of lost neurons, placing
severe constraints on functional recovery. In contrast to the situation in
mature mammals, lower vertebrates retain their regenerative capacity
throughout life. In fish, for example, retinal ganglion cells (RGCs), the pro-
jection neurons of the eye, can regenerate injured axons over long distances to
reinnervate their proper target areas, form synapses in a topographically or-
ganized fashion, and restore function. This phenomenon suggests that at least
some vertebrates retain the capacity for axon growth and guidance through-
out life. Immature mammals likewise retain their regenerative potential, but
this capacity is lost in the early postnatal period (
Chen, Jhaveri, & Schneider,
1995; Goldberg, Klassen, Hua, & Barres, 2002
). Regenerative failure in the
CNS of mature mammals is generally thought to be associated with a
developmental decline in neurons' intrinsic growth capacity, insufficiency
of appropriate trophic factors, and the inhibitory environment formed by
molecules associated with myelin, the perineuronal net, and the astrocytic
scar that forms at the site of injury (
Aguayo, David, & Bray, 1981; Schwab
& Thoenen, 1985; Silver & Miller, 2004; Winzeler et al., 2011; Yiu &
He, 2003
).
1. INTRAOCULAR INFLAMMATION PROMOTES OPTIC
NERVE REGENERATION
A seminal series of studies by Aguayo and colleagues showed that CNS
neurons that normally cannot extend injured axons in their native environ-
ment are able to regenerate axons over long distances through a peripheral
nerve (PN) graft (
Aguayo et al., 1990
). These results have been widely attrib-
uted to an absence of inhibitory molecules in the peripheral nervous system
that normally suppress regeneration in the CNS. Berry and colleagues
