Previous studies of normal monkey LGN have used Nissl stain that
labels all neurons including relay neurons and
interneurons.
4 31 32 In the present study, parvalbumin was
used for specific labeling of relay LGN neurons connecting to the
visual cortex.
23 24 Our cross-sectional neuronal area
measurements for magno- and parvocellular layers were similar to
measurements by Headon et al.
31
According to our results, relay neurons in magno- and
parvocellular layers undergo atrophy in experimental glaucoma. The mean
neuronal shrinkage observed in the two glaucomatous animals with
complete optic nerve fiber loss in this study was similar to that
observed by Matthews
6 12 months after ocular enucleation:
43% vs. 54% in magnocellular layer 1, 49% vs. 66% in parvocellular
layer 4, and 62% vs. 66% in parvocellular layer 6.
The present study demonstrates for the first time in the central
nervous system that cell size decrease relates to the degree of
deafferentation, previously suggested by findings in studies of the
olfactory system
33 and somatosensory sytem.
34 The linear relationship between the degree of optic nerve damage and
degree of atrophy in relay LGN neurons suggests a link between loss of
retinal ganglion cells and shrinkage of their target neurons.
Although significant input to the LGN from the cortex and several
subcortical structures has been described,
35 36 atrophic
changes observed in target relay neurons appears to be directly related
to the loss of connections with RGCs, the major afferent input to the
LGN. In addition, the linear relationship found in this study between
shrinkage of relay neurons and mean IOP is in keeping with the
correlation previously noted between atrophy of Nissl-stained neurons
and mean IOP.
17 We also observed significant neuronal
shrinkage in monkeys with ocular hypertension and no optic nerve fiber
loss, suggesting that neuronal atrophy in the LGN may be an early
event, at least partially related to elevated IOP. Statistical
determination of which of these parameters (i.e., optic nerve fiber
loss or IOP) is more important in atrophy was not possible in this
study, because of the large sample size needed for this type of
analysis.
Our results also suggest that atrophy of relay neurons in parvocellular
layers is greater than that observed in magnocellular layers in
glaucoma. In two monkeys with complete optic nerve fiber loss, neuronal
atrophy was noted in both magno- and parvocellular layers, as may be
expected. In addition, neuronal atrophy appeared to be more severe in
parvocellular layers than in magnocellular layers, in keeping with
previous studies showing that neuronal atrophy is more severe in parvo-
than in magnocellular layers after enucleation
1 6 and
similar to observations in human LGN after enucleation.
37 Investigators in a recent study were unable to detect a differential
cell size effect between magno- and parvocellular neurons in
experimental glaucoma.
17 In addition to overall shorter
survival times compared with that of the present study, the difference
may be due to the criterion used to identify neurons—namely, the
presence of a distinct nucleolus.
17 Because this organelle
is known to shrink during transneuronal degeneration, this criterion
may have introduced a bias in the selection of neurons that show less
atrophy for area measurement.
38 Finally, Nissl stain
labels relay neurons in addition to interneurons. The interneurons,
confined to the LGN, are relatively resistant to transneuronal
degeneration, and interneurons demonstrate less atrophic change
compared with relay neurons after enucleation.
21 22 This, combined with the fact that magnocellular layers are known to
have a greater percentage of interneurons than parvocellular
layers,
19 may also explain why no relative difference in
atrophy between magnocellular and parvocellular layers was detected in
the previous study.
17 In addition, the seven monkeys in
our study each had a longer survival time of 14 months compared with
survival times ranging from 0.5 to 6 months with similar mean
IOP.
17
Neuronal atrophy is believed to precede neuronal loss. Mathews et
al.
4 6 showed that whereas neuronal atrophy occurred
within 6 months after ocular enucleation, loss of neurons was not seen
until 12 months after ocular enucleation. In the present study, the
shrinkage of LGN neurons in experimental glaucoma was found at both
early and advanced stages of glaucomatous damage, and increased in a
linear fashion with optic nerve fiber loss. However, significant loss
of LGN magnocellular neurons (68% and 61%) and parvocellular neurons
(60% and 68%) was restricted to monkeys with optic nerve fiber loss
of 61% and 100%, respectively.
10 That neuronal atrophy
precedes neuronal loss is not supported by the results of a recent
study in which significant neuronal loss in the magnocellular layer was
reported as early as 2.5 weeks after IOP elevation and before the
detection of significant atrophy.
17 This discrepancy is
probably explained by the difficulty in detecting the nucleolus (the
criterion used by the investigators to identify neurons), particularly
in atrophic neurons with shrunken nucleolus.
38
In this study, optic nerve fiber loss ranged from 0% to 100%
and mean optic nerve fiber loss was 45%. Although this range of optic
nerve fiber loss may reflect the full spectrum of glaucomatous optic
nerve damage in humans, further studies are needed to assess the degree
of neuronal atrophy in LGN and its relationship to the degree of optic
nerve fiber loss in human glaucoma.
The presence of degeneration in LGN neurons has several implications
regarding progressive glaucomatous damage. The target neurons may
provide trophic support for RGCs and in fact, damage to LGN neurons has
been shown to cause RGC atrophy and degeneration.
39 The
degeneration of LGN neurons in experimental glaucoma may increase the
susceptibility of surviving RGCs to ongoing damage. Additionally, the
changes in relay LGN neurons that project to visual cortex, may explain
in part the metabolic and neurochemical changes seen in the primary
visual cortex in glaucoma.
15 18 40 41 We propose that in
addition to therapies to rescue RGCs directly, neuroprotective
strategies to rescue LGN neurons in glaucoma may further enhance RGC
survival. Indeed, a neurotrophic factor has been shown to prevent the
atrophy in LGN neurons induced by monocular visual
deprivation.
42 Although the mechanisms underlying neuronal
atrophy are not yet known, understanding the atrophic process in
glaucoma may provide insights into glaucomatous progression and its
prevention.
The authors thank Tamara Arenovich and Barbara Thomson,
Department of Statistics, University of Toronto, for assistance with
statistical analyses.