layers, called parvocellular layers, receive input from P RGCs conveying red–green color information. The koniocellular neurons located between principal layers receive input from K RGCs conveying blue–yellow color information (Kaplan, 2004). Each LGN layer receives input from one eye only: Layers 2, 3, and 5 receive input from the ipsilateral eye, and layers 1, 4, and 6 from the contralateral eye. Within the LGN, approximately 20% of the LGN neurons are GABAergic interneurons remaining in the LGN (Montero and Zempel, 1986), while 80% are relay neurons with their axons forming optic radiations that convey visual information to the primary visual cortex. Only a minority of synaptic inputs onto geniculate relay cells derive from retina (less than 10%), with the majority of synaptic input coming from GABAergic interneurons, cortical, and subcortical inputs (Van Horn et al., 2000).

Mechanisms of RGC injury in glaucoma

The death or loss of RGCs is accepted as the pathological correlate of irreversible vision loss in glaucoma. The loss of RGCs is slow and partial, and accompanied by a specific visual field loss pattern that extends in a progressive manner. Some evidence suggests that RGC death is apoptotic in nature (Quigley, 1999), and primary mechanisms leading to programmed cell death have been reviewed elsewhere (Weinreb and Khaw, 2004). Our understanding of this process is based on experimental work performed in glaucoma models with elevated IOP and optimized over the years to study the sequence of pathological events triggered by IOP elevation (Morrison et al., 1997; Gabelt et al., 2003; Lindsey and Weinreb, 2005; Weinreb and Lindsey, 2005). These pathological events associated with RGC death include glial cell alteration at the optic nerve head, disruption of intracellular transport mechanisms leading to growth factor deprivation, oxidative stress, glutamate excitotoxicity, immune alterations, and vascular pathology (Weinreb and Khaw, 2004; Nickells, 2007; Feilchenfeld et al., 2008) (Fig. 2). However, careful examination of the retina and optic nerve in these models and human glaucoma indicates that a significant

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proportion of RGCs are neither dead nor completely healthy and that surviving RGCs show subtle morphological changes including shrinkage of cell body, dendrites, and axons (Weber et al., 1998; Morgan et al., 2000). Morphological changes correlated with altered function (Weber and Harman, 2005), and it is possible that these early changes contribute to visual dysfunction in glaucoma. The relationship between IOP elevation and these changes is not completely elucidated, and there is no clear evidence to suggest that dysfunctional cells are destined to die. Factors implicated in RGC death may also be relevant to early injury and cell changes.

Transsynaptic degeneration of the lateral geniculate nucleus in glaucoma

In several neurodegenerative diseases, central nervous system (CNS) injury spreads from a population of neurons to other neuronal populations along anatomical and functional connections (Saper et al., 1987; Kume et al., 1993; Suzuki et al., 1995; Su et al., 1997). This process, called transsynaptic or transneuronal degeneration, is critical to disease progression in many neurological disorders, such as neurons involved in cognition in Alzheimer’s disease (Su et al., 1997). A striking example of this process is in the visual system where transsynaptic degeneration has been observed in the LGN in humans following removal of the eye, a total deafferentation severing all RGC axons (Goldby, 1957). Systematic studies of this process following unilateral enucleation in nonhuman primates demonstrated atrophy of LGN neurons in all animals (Matthews et al., 1960) and loss of LGN neurons in those with longer survival time (Matthews, 1964).

Studies of transsynaptic degeneration in glaucoma come mainly from the experimental monkey model of glaucoma. In this model, the fluid drainage pathway of the eye, the trabecular meshwork, is lasered excessively by argon laser trabeculoplasty, inducing scarring and restricting fluid exit from the eye (Gaasterland and Kupfer, 1974). This caused IOP elevation, typically induced in one eye, after which eye pressure is monitored in both

glaucoma is highly relevant to human disease due to similar anatomy and physiology of central visual pathways (Kaplan, 2004); mimicking of characteristic glaucomatous optic nerve changes observed in human glaucoma (Quigley et al., 1981; Yu¨cel et al., 1999; Gabelt et al., 2003) and monkeys trained to perform reliable visual field testing show visual deficits similar to those observed in patients with glaucoma (Harwerth et al., 2002). In addition to IOP, optic disk changes (Yu¨cel et al., 1998; Burgoyne et al., 2002; Hare et al., 2004) and visual electrophysiological changes (Frishman et al., 1996; Hare et al., 1999) can be monitored in vivo. After exposure to elevated IOP, postmortem retina and optic nerve are studied to assess pathological events in these tissues. Chronic elevated IOP in the primate model induces blocked anterograde transport to the LGN and retrograde transport at the level of the lamina cribrosa (Quigley and Anderson, 1976; Gaasterland, 1978; Quigley and Addicks, 1980; Radius and Anderson, 1981a, b), leading to RGC death (Quigley, 1999), and atrophy of

surviving cell bodies and dendrites (Weber et al., 1998; Morgan et al., 2000). Although axon size measurement suggested selective loss of larger neurons (Glovinsky et al., 1991), presumably M RGCs, atrophy of RGC axons (Morgan et al., 2000) was not considered.

In experimental primate glaucoma, varying degrees of RGC loss measured by established histomorphometric techniques can be observed (Fig. 4). This includes no evidence of RGC loss with elevated IOP, or partial loss of RGCs, and even total RGC loss with replacement by glial scar (Yu¨cel et al., 1999).

Glaucomatous RGC loss and atrophy spread by anterograde degeneration to major visual pathways in the brain (Gupta and Yu¨cel, 2003).

Neural degeneration in magno-, parvo-, and koniocellular LGN layers

Following elevated IOP in the monkey eye, metabolic changes have been noted in the LGN layers connected to the glaucomatous eye (Vickers

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et al., 1997; Crawford et al., 2000). Loss of magnoand parvocellular relay neurons in this model occurred (Weber et al., 2000; Yu¨cel et al., 2000) and increased with optic nerve fiber loss and mean IOP (Yu¨cel et al., 2003) (Fig. 5). Surviving neurons showed atrophy that also increased with these parameters (Yu¨cel et al., 2001), more pronounced in parvocellular layers (Yu¨cel et al., 2001). The latter was even observed in monkeys with ocular hypertension without detectable optic nerve fiber loss (Yu¨cel et al., 2001). In fact, this group also showed reduced LGN dendrite complexity and field area (Gupta et al., 2007), indicating that not all changes are attributable to deafferentation of the visual system.

In the koniocellular pathway, the alpha subunit of type II calmodulin-dependent protein kinase (CaMK-II alpha), a selective marker for these neurons and a major postsynaptic density protein (Hendry and Reid, 2000), was reduced in primate glaucoma (Yu¨cel et al., 2003). Decreased immunoreactivity was observed also in ocular hypertensive monkeys without evidence of optic nerve fiber loss

(Yu¨cel et al., 2003). This finding suggests that neurochemical alterations at the synaptic level occur at early stages of LGN injury to this blue–yellow pathway. Thus, transsynaptic degeneration of the LGN in primate glaucoma appears to affect the three major vision channels, namely the magno-, parvo-, and koniocellular pathways (Yu¨cel et al., 2003).

While changes to relay neurons in experimental glaucoma are described above, it is not known whether GABAergic interneurons in the LGN are also altered in glaucoma as has been observed following enucleation and monocular deprivation (Hendry, 1991).

Glial cells including astrocytes and NG2 cells also appeared altered in experimental glaucoma involving the optic tract and LGN (Yu¨cel et al., unpublished data). Further studies are needed to characterize the involvement of other cell types such as microglia (Wang et al., 2000), vascular (Luthra et al., 2005), and perivascular cells in the LGN in glaucoma.

Mechanisms related to transsynaptic degeneration in glaucoma may be relevant to strategies