The Open Ophthalmology Journal




ISSN: 1874-3641 ― Volume 13, 2019

Comparative Anatomy of the Optic Nerve Head and Inner Retina in Non-Primate Animal Models Used for Glaucoma Research



Christian Albrecht May*
Department of Anatomy, Medical Faculty Carl Gustav Carus, Technical University Dresden, D-01307 Dresden, Germany

Abstract

To judge the information of experimental settings in relation to the human situation, it is crucial to be aware of morphological differences and peculiarities in the species studied. Related to glaucoma, the most important structures of the posterior eye segment are the optic nerve head including the lamina cribrosa, and the inner retinal layers. The review highlights the differences of the lamina cribrosa and its vascular supply, the prelaminar optic nerve head, and the retinal ganglion cell layer in the most widely used animal models for glaucoma research, including mouse, rat, rabbit, pig, dog, cat, chicken, and quail. Although all species show some differences to the human situation, the rabbit seems to be the most problematic animal for glaucoma research.

Keywords: Morphology, lamina cribrosa, optic nerve head, inner retina, animal models.


Article Information


Identifiers and Pagination:

Year: 2008
Volume: 2
First Page: 94
Last Page: 101
Publisher Id: TOOPHTJ-2-94
DOI: 10.2174/1874364100802010094

Article History:

Received Date: 26/3/2008
Revision Received Date: 17/4/2008
Acceptance Date: 28/4/2008
Electronic publication date: 9/5/2008
Collection year: 2008

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© Christian Albrecht May; Licensee Bentham Open.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.


* Address correspondence to this author at the Anatomisches Institut, Fetscherstr. 74, D-01307 Dresden, Germany; Tel: +49-351-458-6105; Fax: +49-351-458-6303; E-mail: albrecht.may@mailbox.tu-dresden.de




Glaucoma is a chronic disease appearing in a number of different conditions that are merged pathologically by the degeneration of retinal ganglion cells and their processes within the optic nerve and clinically by specific changes in the optic nerve head region and loss of vision.

Since one major risk factor is the occurrence of an elevated intraocular pressure (IOP), and since IOP is substantially regulated by the aqueous outflow pathway tissue, a general classification of different types of glaucoma relates to clinical and morphological findings in the anterior chamber angle region. In human eyes, the most common form is the primary open angle glaucoma (POAG) of the aged adult. Other primary forms include closed angle glaucoma and congenital forms of glaucoma, although this concept is softened with the recognition of a multitude of so called ‘secondary’ glaucomas due to various definable initial events.

I. ANIMAL MODELS USED IN GLAUCOMA RESEARCH

The same classification that is used in human eyes has been introduced for animal models of glaucoma and ocular hypertension. In a review on anterior segment differences by Chew [1Chew SJ. Krupin Animal models of glaucoma In: Ritch R, Shields MB, Eds. In: The Glaucomas. St. Louis Missouri: Mosby year book Inc 1996; Vol.I: pp. 55-69.], glaucoma was subdivided into inherited, which is rare in all animals except the anterior chamber dysgenic syndromes, congenital, and induced glaucoma, the latter mentioned being the most frequently used group in animal glaucoma research. Induced glaucoma considers the fact that substantial elevated IOP leads to glaucomatous changes in the posterior eye segment. The animals used in these studies are mostly mammals, including mouse, rat, rabbit, pig, dog, cat, and monkey, or birds, including chicken and quail. Although most animals show changes that were considered to be comparable to a glaucomatous situation, it is difficult to correlate these findings with the human situation. One issue in this respect is the different anatomy and morphology not only in the anterior eye segment but also in the lamina cribrosa region and in the inner layer of the retina. To help judging the research findings in these models the present paper reviews the different anatomical situations in the above mentioned animals presently being used in glaucoma research.

II. COMPARATIVE ANATOMY OF THE LAMINA CRIBROSA (LC)

Although numerous species develop a LC (Table 1), one of the most widely used animal model, the mouse, does not develop connective tissue bundles through the optic nerve head at the level of the sclera [2Tansley K. Comparison of the lamina cribrosa in mammalian species with good and with indifferent vision Br J Ophthalmol 1956; 40: 178-82.-5May CA, Lütjen-Drecoll E. Morphology of the murine optic nerve Invest Ophthalmol Vis Sci 2002; 43: 2206-12.]. This finding is independent of the different mouse strains analyzed. In the rat with an optic nerve head diameter at the level of the sclera only slightly larger than that of the mouse, single collagen bundles are present forming a lamina-cribrosa like structure. The quantity of the LC at the level of the sclera seems dependent on the different strains: a substantial LC was reported in the Brown Norway rat [6Morrison J, Farrell S, Johnson E, Deppmeier L, Moore CG, Grossmann E. Structure and composition of the rodent lamina cribrosa Exp Eye Res 1995; 60: 127-35.] and in the Long Evans rat [7Hildebrand C, Remahl S, Waxman G. Axo-glial relations in the retina-optic nerve junction of the adult rat: electron-microscopic observations J Neurocytol 1985; 14: 597-617.], whereas the PVG Hooded rat [8Johansson JO. The lamina cribrosa in the eyes of rats, hamsters, gerbils and guinea pigs Acta Anat (Basel) 1987; 128: 55-62.] and Wistar rat [9May CA. The optic nerve head region of the aged rat: an immunohistochemical investigation Curr Eye Res 2003; 26: 347-54.] seem to contain only sparse LC bundles.

Table 1

Occurrence and Distribution Differences in the Lamina Cribrosa (LC) of Animals Used in Glaucoma Research




Table 2

Variation of the Central Retinal Vessels – Number and Location at the Optic Disc




Table 3

Blood Supply of the Optic Nerve Head Region




Table 4

Comparative Data of the Inner Retina




The lack of the LC in the mouse cannot be explained solely by size-dependent mechanical properties since species with much larger optic nerve head diameters, but myelinated axons reaching into the nerve fiber layer of the retina, also show only a sparse LC. This group of animals includes the rabbit [4Morcos Y, Chan-Ling T. Concentration of astrocytic filaments at the retinal optic nerve junction is coincident with the absence of intra-retinal myelination: comparative and developmental evidence J Neurocytol 2000; 29: 665-78.,10Bunt-Milam AH, Dennis MB Jr, Bensinger RE. Optic nerve head axonal transport in rabbits with hereditary glaucoma Exp Eye Res 1987; 44: 537-1.], quail, and chicken [4Morcos Y, Chan-Ling T. Concentration of astrocytic filaments at the retinal optic nerve junction is coincident with the absence of intra-retinal myelination: comparative and developmental evidence J Neurocytol 2000; 29: 665-78.]. In these species, the optic nerve head contains neuronal tissue and astrocytes in addition to oligodendroglia cells [11Morcos Y, Chan-Ling T. Identification of oligodendrocyte precursors in the myelinated streak of the adult rabbit retina in vivo Glia 1997; 21: 163-82.-13Quesada A, Prada FA, Aguilera Y, Espinar A, Carmona A, Prada C. Peripapillary glial cells in the chick retina A special glial cell type expressing astrocyte, radial glia, neuron, and oligodendrocyte markers throughout development Glia 2004; 46: 346-55.].

A multi-layered LC with close three-dimensional similarities to the primate LC is described in the pig [14Brooks DE, Arellano E, Kubilis PS, Komaromy AM. Histomorphometry of the porcine scleral lamina cribrosa surface Vet Ophthalmol 1998; 1: 129-35.], cat [4Morcos Y, Chan-Ling T. Concentration of astrocytic filaments at the retinal optic nerve junction is coincident with the absence of intra-retinal myelination: comparative and developmental evidence J Neurocytol 2000; 29: 665-78.,15Radius RL, Bade B. Axonal transport interruption and anatomy at the lamina cribrosa Arch Ophthalmol 1982; 100: 1661-4.,16Radius RL, Bade B. The anatomy at the lamina cribrosa in the normal cat eye Arch Ophthalmol 1982; 100: 1658-60.], and dog eye [17Brooks DE, Samuelson DA, Gelatt KN, Smith PJ. Morphologic changes in the lamina cribrosa of beagles with primary open-angle glaucoma Am J Vet Res 1989; 50: 936-41.]. The size of the LC diameter (Table 1) and the variability of the single pores within the LC are comparable in all three species and, again, match the situation in the primate.

III. COMPARATIVE COMPOSITION OF THE LAMINA CRIBROSA

As only qualitative studies are present to date, the comparison of various lamina cribrosa components between species is suggestive.

Immunohistochemical analysis of the extracellular matrix composition of the laminar beams within the LC shows the presence of collagen types I, III, VI, and elastin in the beams, and laminin and collagen type IV (basal membranes) at the border to the astrocytes and around the vessels. This composition is so far only studied in the rat [6Morrison J, Farrell S, Johnson E, Deppmeier L, Moore CG, Grossmann E. Structure and composition of the rodent lamina cribrosa Exp Eye Res 1995; 60: 127-35.,9May CA. The optic nerve head region of the aged rat: an immunohistochemical investigation Curr Eye Res 2003; 26: 347-54.], monkey [18Morrison JC, Jerdan JA, L'Hernault NL, Quigley HA. The extracellular matrix composition of the monkey optic nerve head Invest Ophthalmol Vis Sci 1988; 29: 1141-50.-22Hernandez MR. Ultrastructural immunocytochemical analysis of elastin in the human lamina cribrosa. Changes in elastic fibers in primary open-angle glaucoma Invest Ophthalmol Vis Sci 1992; 33: 2891-903.] and human [23Ye H, Yang J, Hernandez MR. Localization of collagen type III mRNA in normal human optic nerve heads Exp Eye Res 1994; 58: 53-63.-28Albon J, Karwatowski WS, Easty DL, Sims TJ, Duance VC. Age related changes in the non-collagenous components of the extracellular matrix of the human lamina cribrosa Br J Ophthalmol 2000; 84: 311-7.]. In addition to these electron-microscopically viewable components, chondroitin and dermatan sulfate proteoglycans were localized in the rat [6Morrison J, Farrell S, Johnson E, Deppmeier L, Moore CG, Grossmann E. Structure and composition of the rodent lamina cribrosa Exp Eye Res 1995; 60: 127-35.], monkey [29Fukuchi T, Sawaguchi S, Yue BY, Iwata K, Hara H, Kaiya T. Sulfated proteoglycans in the lamina cribrosa of normal monkey eyes and monkey eyes with laser-induced glaucoma Exp Eye Res 1994; 58: 231-43.] and human LC [30Sawaguchi S, Yue BY, Fukuchi T, Iwata K, Kaiya T. Sulfated proteoglycans in the human lamina cribrosa Invest Ophthalmol Vis Sci 1992; 33: 2388-98.,31Sawaguchi S, Yue BY, Fukuchi T, Iwata K, Kaiya T. Age-related changes of sulfated proteoglycans in the human lamina cribrosa Curr Eye Res 1993; 12: 685-92.].

Although the observations warrant further studies utilizing more quantitative techniques, the description in the amount of collagen type VI varies in different species studied: whereas only weak collagen type V and VI is described in the normal human LC [27Jeffery G, Evans A, Albon J, Duance V, Neal J, Dawidek G. The human optic nerve: fascicular organisation and connective tissue types along the extra-fascicular matrix Anat Embryol (Berl) 1995; 191: 491-502.], intense staining for collagen type VI is documented for the normal rat [6Morrison J, Farrell S, Johnson E, Deppmeier L, Moore CG, Grossmann E. Structure and composition of the rodent lamina cribrosa Exp Eye Res 1995; 60: 127-35.,9May CA. The optic nerve head region of the aged rat: an immunohistochemical investigation Curr Eye Res 2003; 26: 347-54.] and dog LC [32Brooks DE, Komaromy AM, Garcia-Fernandez MC, Cutler TJ, Samuelson DA, Kallberg ME. Immunohistochemistry of the extracellular matrix of the normal equine lamina cribrosa Vet Ophthalmol 2000; 3: 127-32.].

Unfortunately there is a complete lack of data on the composition of the LC in the other animals used for glaucoma research including rabbit, pig, cat, quail, and chicken.

IV. COMPARATIVE ANATOMY OF THE CENTRAL RETINAL VESSELS (TABLE 2)

In rodents (mouse, rat), the central retinal artery (CRA) is derived from a branch of the ophthalmic artery prior to its ramification into the posterior ciliary arteries. A v-shaped intra-arterial cushion is regularly present in the ophthalmic artery just before the branching of the CRA that might influence the vascular flow in this specific region [5May CA, Lütjen-Drecoll E. Morphology of the murine optic nerve Invest Ophthalmol Vis Sci 2002; 43: 2206-12.,33Lassmann H, Pamperl H, Stockinger G. Morphological-functional aspects of intima pads in the rat ophthalmic artery Z Mikrosk Anat Forsch 1972; 85: 139-48.,34Bisaria KK, Sud SD. The central retinal artery in the albino rats (a histological study) Indian J Ophthalmol 1977; 24: 23-6.]. The CRA runs towards the sclera and enters the optic nerve obliquely at the level of the sclera and choroid towards the center of the ONH where it branches further forming the retinal arteries. The central retinal vein (CRV) runs closer to the optic nerve than the artery and is connected with the pial venous system [5May CA, Lütjen-Drecoll E. Morphology of the murine optic nerve Invest Ophthalmol Vis Sci 2002; 43: 2206-12.,35Morrison JC, Johnson EC, Cepurna WO, Funk RH. Microvasculature of the rat optic nerve head Invest Ophthalmol Vis Sci 1999; 40: 1702-9.,36Sugiyama K, Gu ZB, Kawase C, Yamamoto T, Kitazawa Y. Optic nerve and peripapillary choroidal microvasculature of the rat eye Invest Ophthalmol Vis Sci 1999; 40: 3084-90.].

A special situation is present in the rabbit eye that shows an incompletely vascularized retina restricted to the myelinated portion of the nerve fiber layer [37De Schaepdrijver L, Simoens P, Lauwers H, De Geest JP. Retinal vascular patterns in domestic animals Res Vet Sci 1989; 47: 34-42.]. Posterior to the sclera, two to three posterior ciliary arteries form an incomplete arterial circle from which one CRA araises [38Sugiyama K, Bacon DR, Morrison JC, Van Buskirk EM. Optic nerve head microvasculature of the rabbit eye Invest Ophthalmol Vis Sci 1992; 33: 2251-61.]. The venous drainage, in contrast, does not form one main vessel but several branches leaving the retina at the periphery of the ONH. Two prominent veins leave the retina at the nasal and temporal side of the ONH, whereas the superior and inferior branches are much smaller [38Sugiyama K, Bacon DR, Morrison JC, Van Buskirk EM. Optic nerve head microvasculature of the rabbit eye Invest Ophthalmol Vis Sci 1992; 33: 2251-61.].

An almost complementary arrangement of the large retinal vessels described in the rabbit is seen in the pig and dog, where both animals possess a holangiotic retina. In these species, a circulus arteriosus is present around the optic nerve forming several choroidoretinal arteries. From these vessels, up to 6 branches enter the optic nerve head at the level of the sclera and run lateral in the ONH towards the retina [39Simoens P. Morphologic study of the vasculature in the orbit and eyeball of the pig Thesis. : Ghent1985.]. There is no formation of a single CRA. The retinal veins, however, drain the deoxygenated blood towards the center of the ONH forming one CRV that leaves the eye through the LC region [39Simoens P. Morphologic study of the vasculature in the orbit and eyeball of the pig Thesis. : Ghent1985.,40Ammann K, Pelloni G. Das Auge des Hundes Schweiz Arch Tierheilkd 1971; 113: 287-90.].

In the cat eye, the arterial supply of the retina is similar to that described for the pig and the dog [41Wong VG, Macri FJ. Vasculature of the cat eye Arch Ophthalmol 1964; 72: 351-8.-43Risco JM, Nopanitaya W. Ocular microcirculation. Scanning electron microscopic study Invest Ophthalmol Vis Sci 1980; 19: 5-12.]: several cilioretinal arteries send branches to the retina in the lateral portion of the ONH. In contrast to the pig and dog, the main retinal veins in the cat eye do not unite in the center of the ONH but leave the eye parallel to the arteries as separate vessels at the lateral portion of the ONH.

Birds (chicken, quail) have an avascular retina which receives its oxygen by a unique vitreal blood vessel aggregation called a pecten. The vessels within the pecten show typical characteristics seen also in retinal and brain vessels by forming a tight-junction barrier [44Gerhardt H, Liebner S, Wolburg H. The pecten oculi of the chicken as a new in vivo model of the blood-brain barrier Cell Tissue Res 1996; 285: 91-100., 45Liebner S, Gerhardt H, Wolburg H. Maturation of the blood-retina barrier in the developing pecten oculi of the chicken Brain Res Dev Brain Res 1997; 100: 205-19.]. The vessels supplying the pecten run lateral of the ONH and consist of several arterial and venous branches [46Uehara M, Oomori S, Kitagawa H, Ueshima T. The development of the pecten oculi in the chick Nippon Juigaku Zasshi 1990; 52: 503-12., 47Matsunaga N, Amemiya T. Pecten of the chick eye demonstrated by vascular casts Okajimas Folia Anat Jpn 1990; 67: 263-70.].

The central retinal vessels of the primate arise from one CRA and one CRV. The CRA branches from the ophthalmic artery and enters the optic nerve posteriorly to the LC. The CRV runs parallel with the artery through the LC. Both vessels branch in the center of the ONH forming the main retinal vessels.

V. COMPARATIVE ANATOMY OF THE OPTIC NERVE HEAD BLOOD SUPPLY

Due to the difficulties of physiological measurements in this specific region, the data presented is based on corrosion cast preparations and serial sections through the optic nerve head region. Although the number and size of the vessels might indicate the higher or lower importance of the source forming the microvasculature in the optic nerve head region, the precise physiological and patho-physiological role remains hypothetical. The differences between the species are summarized in Table 3.

In the mouse, both corrosion cast preparations and serial sections revealed that the supply of the optic nerve head is exclusively from recurrent branches of the retina [5May CA, Lütjen-Drecoll E. Morphology of the murine optic nerve Invest Ophthalmol Vis Sci 2002; 43: 2206-12.]. Neither the choroid nor the pial vessels contribute to this region. In the rat, most of the vessels in the optic nerve head emanate from the retina, too, but some infrequent branches were also observed deriving from the pial vessels [33Lassmann H, Pamperl H, Stockinger G. Morphological-functional aspects of intima pads in the rat ophthalmic artery Z Mikrosk Anat Forsch 1972; 85: 139-48.,34Bisaria KK, Sud SD. The central retinal artery in the albino rats (a histological study) Indian J Ophthalmol 1977; 24: 23-6.]. There is conflict data regarding vessels in the optic nerve head region deriving from the choroid using corrosion cast preparations: some authors observed branches [35Morrison JC, Johnson EC, Cepurna WO, Funk RH. Microvasculature of the rat optic nerve head Invest Ophthalmol Vis Sci 1999; 40: 1702-9.] while others denied their existence [36Sugiyama K, Gu ZB, Kawase C, Yamamoto T, Kitazawa Y. Optic nerve and peripapillary choroidal microvasculature of the rat eye Invest Ophthalmol Vis Sci 1999; 40: 3084-90.]. Semithin serial sections through the optic nerve head of Wistar rats did not show vascular branches originating from the choroid but some branches from the posterior ciliary arteries prior to their branching in the choroid (own unpublished data). Further comparative studies are needed to clarify if the different observations are due to different rat strains investigated or due to different methodologies.

A completely different supply of the optic nerve head is observed in the rabbit: most of the smaller vessels show clear arterial and venous connections with the choroid [38Sugiyama K, Bacon DR, Morrison JC, Van Buskirk EM. Optic nerve head microvasculature of the rabbit eye Invest Ophthalmol Vis Sci 1992; 33: 2251-61.]. Next to branches from the arterial circle forming the pial vessels, single branches derive from the central retinal artery within the optic nerve head [38Sugiyama K, Bacon DR, Morrison JC, Van Buskirk EM. Optic nerve head microvasculature of the rabbit eye Invest Ophthalmol Vis Sci 1992; 33: 2251-61.].

Pig, dog and cat show a remarkably similar supply of the optic nerve head region: since they do not possess a single central retinal artery but rather several branches deriving from a plexus of cilioretinal arteries, the main vessels derive from the pial vessels which are in direct contact with the cilioretinal vascular plexus, and from choroidal vessels of the same source [39Simoens P. Morphologic study of the vasculature in the orbit and eyeball of the pig Thesis. : Ghent1985., 41Wong VG, Macri FJ. Vasculature of the cat eye Arch Ophthalmol 1964; 72: 351-8.-43Risco JM, Nopanitaya W. Ocular microcirculation. Scanning electron microscopic study Invest Ophthalmol Vis Sci 1980; 19: 5-12.]. The central retinal arteries and the retina are not involved in the supply of the optic nerve head even in the innermost layer towards the retina (in detail only shown for the pig optic nerve head [39Simoens P. Morphologic study of the vasculature in the orbit and eyeball of the pig Thesis. : Ghent1985.]).

In birds (chicken, quail), no data exists about the fine vascular supply of the optic nerve head region.

The vascular supply of the optic nerve head in primates was first introduced by Hayreh [48Hayreh SS. Anatomy and physiology of the optic nerve head Trans Am Acad Ophthalmol Otolaryngol 1974; 78: OP240-54.] using corrosion cast preparations of cynomolgus and rhesus monkeys. In his scheme of arterial blood supply he highlights the influence of all three sources, namely retinal, choroidal, and pial arteries [48Hayreh SS. Anatomy and physiology of the optic nerve head Trans Am Acad Ophthalmol Otolaryngol 1974; 78: OP240-54.]. If the choroidal arteries play the same role in the human eye is not definitely answered: some literature exists on human eyes that questions the involvement of the choroid [49Zhao Y, Li FM. Microangioarchitecture of optic papilla Jpn J Ophthalmol 1987; 31: 147-59.]. The retrolaminar optic nerve in non-human primates and human is mainly supplied by branches deriving from the arterial ‘circle’ of Haller and Zinn formed by anastomoses of the short posterior ciliary arteries [50Olver JM, Spalton DJ, McCartney AC. Quantitative morphology of human retrolaminar optic nerve vasculature Invest Ophthalmol Vis Sci 1994; 35: 3858-66.,51Hayreh SS. Blood supply of the optic nerve head Ophthalmologica 1996; 210: 285-95.].

VI. COMPARATIVE ANATOMY OF THE GANGLION CELL LAYER (TABLE 4)

Although the gross morphology of the retinal layers is the same in all animals used for glaucoma research, clear differences are present in the inner retina, mainly in the appearance of the ganglion cell layer (GCL). As a general feature in all retinae, ‘displaced’ amacrine cells are present in the GCL with different relative numbers compared to the ganglion cell counts. Their specific role within the GCL has not yet been determined but their inter-species existence might point to a specific role in the GCL and thus upgrade their role as purely ‘displaced’. Since accurate determination of the functional differences between the different amacrine cell classes is difficult, their neurohistochemical profile is required for a more comprehensive explanation of their role.

Most profound variations in the number of ganglion cells are present in different mouse strains: they vary between 32,000 and 87,000 [52Williams RW, Strom RC, Rice DS, Goldowitz D. Genetic and environmental control of variation in retinal ganglion cell number in mice J Neurosci 1996; 16: 7193-205.]. This strain-variation is less pronounced in the rat, but differences between albino (more than 100,000) and pigmented animals (72,000) were also reported to be significant [53Hunter A, Bedi KS. A quantitative morphological study of interstrain variation in the developing rat optic nerve J Comp Neurol 1986; 245: 160-6.,54Cavallotti C, Cavallotti D, Pescosolido N, Pacella E. Age-related changes in rat optic nerve morphological studies Anat Histol Embryol 2003; 32: 12-6.]. However, different studies on pigmented animals exist in the literature that might lead to the conclusion that the total number of ganglion cells among different rat strains is more consistence at around 90,000-120,000 [55Hughes A. The pigmented-rat optic nerve: fibre count and fibre diameter spectrum J Comp Neurol 1977; 176: 263-8.-58Bedi KS, Warren MA. The effects of undernutrition during early life on the rat optic nerve fibre number and size-frequency distribution J Comp Neurol 1983; 219: 125-32.]. Both rodents not only contain ganglion cells in the GCL but numerous displaced amacrine cells, which make up to 59% in the mouse [59Jeon CJ, Strettoi E, Masland RH. The major cell populations of the mouse retina J Neurosci 1998; 18: 8936-46.] and 50% in the rat [60Perry VH. Evidence for an amacrine cell system in the ganglion cell layer of the rat retina Neuroscience 1981; 6: 931-44.,61Perry VH, Henderson Z, Linden R. Postnatal changes in retinal ganglion cell and optic axon populations in the pigmented rat J Comp Neurol 1983; 219: 356-68.].

In the rabbit retina, one profound finding is the restriction of the vessels to the vascular streak and an otherwise avascular retina. This also leads to a restriction of astrocytes in the retina: they are only present in the myelinated region of the vascular streak [62Schnitzer J. The development of astrocytes and blood vessels in the postnatal rabbit retina J Neurocytol 1988; 17: 433-9.]. The number of ganglion cells in different albino strains varies between 291,000 [63Robinson SR, Horsburgh GM, Dreher B, McCall MJ. Changes in the numbers of retinal ganglion cells and optic nerve axons in the developing albino rabbit Brain Res 1987; 432: 161-74.] and 394,000 [64Vaney DI, Hughes A. The rabbit optic nerve fibre diameter spectrum, fibre count, and comparison with a retinal ganglion cell count J Comp Neurol 1976; 170: 241-51.] showing an accumulation in the area centralis [65Oyster CW, Takahashi ES, Hurst DC. Density, soma size, and regional distribution of rabbit retinal ganglion cells J Neurosci 1981; 1: 1331-46.] and is comparable to pigmented animals (250,000 – 270,000 [66Provis JM. The distribution and size of ganglion cells in the retina of the pigmented rabbit: a quantitative analysis J Comp Neurol 1979; 185: 121-37.]). The number of displaced amacrine cells in the GCL of rabbits is lower than in rodents at around 31,7% [67Vaney DI. A quantitative comparison between the ganglion cell populations and axonal outflows of the visual streak and periphery of the rabbit retina J Comp Neurol 1980; 189: 215-33.,68Vaney DI, Peichi L, Boycott BB. Matching populations of amacrine cells in the inner nuclear and ganglion cell layers of the rabbit retina J Comp Neurol 1981; 199: 373-91.].

More pronounced than in the rabbit, the retina of birds (chicken, quail) is completely avascular. A specific glia-cell barrier (peripapillary glia) prevents the vessels from entering into the retina [69Schuck J, Gerhardt H, Wolburg H. The peripapillary glia of the optic nerve head in the chicken retina Anat Rec 2000; 259: 263-75.]. Similar to the rabbit, partly myelinated axons are localized in the nerve fiber layer in both the quail and the chicken retina [70Seo JH, Haam YG, Park SW, et al. Oligodendroglia in the avian retina: immunocytochemical demonstration in the adult bird J Neurosci Res 2001; 65: 173-83.,71Fujita Y, Imagawa T, Uehara M. Fine structure of the retino-optic nerve junction in the chicken Tissue Cell 2001; 33: 129-34.]. Subsequently, oligodendrocytes are located throughout the avian retina with a distinct central-to-peripheral gradient [70Seo JH, Haam YG, Park SW, et al. Oligodendroglia in the avian retina: immunocytochemical demonstration in the adult bird J Neurosci Res 2001; 65: 173-83.,72Quesada A, Prada FA, Aguilera Y, Espinar A, Carmona A, Prada C. Peripapillary glial cells in the chick retina A special glial cell type expressing astrocyte, radial glia, neuron, and oligodendrocyte markers throughout development Glia 2004; 46: 346-55.]. The number of ganglion cells in the avian retina is high and is about twice that of primates (quail: 2,000,000 ganglion cells [73Ikushima M, Watanabe M, Ito H. Distribution and morphology of retinal ganglion cells in the Japanese quail Brain Res 1986; 376: 320-4.]; chicken: 2,400,000 ganglion cells [74Rager G, Rager U. Systems-matching by degeneration. I. A quantitative electron microscopic study of the generation and degeneration of retinal ganglion cells in the chicken Exp Brain Res 1978; 33: 65-78.]). In contrast to mammals, there is contrary report about the presence of displaced amacrine cells in the GCL of the bird retina. While almost no amacrines were reported in the quail [73Ikushima M, Watanabe M, Ito H. Distribution and morphology of retinal ganglion cells in the Japanese quail Brain Res 1986; 376: 320-4.], up to 35% of all cells in the GCL were reported to be amacrine in the chicken [75Ehrlich D, Morgan IG. Kainic acid destroys displaced amacrine cells in post-hatch chicken retina Neurosci Lett 1980; 17: 43-8.,76Layer PG, Vollmer G. Lucifer yellow stains displaced amacrine cells of the chicken retina during embryonic development Neurosci Lett 1982; 31: 99-104.].

The number of retinal ganglion cells in the pig (442,629 cells [77Herron MA, Martin JE, Joyce JR. Quantitative study of the decussating optic axons in the pony, cow, sheep, and pig Am J Vet Res 1978; 39: 1137-9.]) and the number of displaced amacrine cells in the GCL (31% [78Komaromy AM, Brooks DE, Kallberg ME, et al. Long-term effect of retinal ganglion cell axotomy on the histomorphometry of other cells in the porcine retina J Glaucoma 2003; 12: 307-15.]) is comparable to that in the rabbit. In contrast to the latter, however, the pig has a holangiotic retina [39Simoens P. Morphologic study of the vasculature in the orbit and eyeball of the pig Thesis. : Ghent1985.] and no intraretinal myelinization of axons. The distribution of astrocytes in the porcine inner retina is similar to that observed in the human eye [79Ruiz-Ederra J, Hitchcock PF, Vecino E. Two classes of astrocytes in the adult human and pig retina in terms of their expression of high affinity NGF receptor (TrkA) Neurosci Lett 2003; 337: 127-30.], the cells firmly ensheathing the vessel circumference [80Rungger-Brandle E, Messerli JM, Niemeyer G, Eppenberger HM. Confocal microscopy and computer-assisted image reconstruction of astrocytes in the mammalian retina Eur J Neurosci 1993; 5: 1093-6.].

In the two carnivores, the number of retinal ganglion cells is 148,303 in the dog [81Brooks DE, Strubbe DT, Kubilis PS, MacKay EO, Samuelson DA, Gelatt KN. Histomorphometry of the optic nerves of normal dogs and dogs with hereditary glaucoma Exp Eye Res 1995; 60: 71-89.] and 193,000 in the cat [82Hughes A, Wassle H. The cat optic nerve: fibre total count and diameter spectrum J Comp Neurol 1976; 169: 171-84.]. In comparison to the eye size, the density of ganglion cells in the dog and cat eye is low. However, both species develop an area centralis with accumulation of retinal ganglion cells (dog [83Hogan D, Williams RW. Analysis of the retinas and optic nerves of achiasmatic Belgian sheepdogs J Comp Neurol 1995; 352: 367-80.,84McGreevy P, Grassi TD, Harman AM. A strong correlation exists between the distribution of retinal ganglion cells and nose length in the dog Brain Behav Evol 2004; 63: 13-22.], cat [85Rapaport DH, Stone J. The area centralis of the retina in the cat and other mammals: focal point for function and development of the visual system Neuroscience 1984; 11: 289-301.,86Robinson SR. Ontogeny of the area centralis in the cat J Comp Neurol 1987; 255: 50-67.]). In addition, the cat is the most intensively studied animal in regards to retinal ganglion cell differentiation [87Cleland BG, Harding TH, Tulunay-Keesey U. Visual resolution and receptive field size examination of two kinds of cat retinal ganglion cell Science 1979; 205: 1015-7.-97Isayama T, Berson DM, Pu M. Theta ganglion cell type of cat retina J Comp Neurol 2000; 417: 32-48.] and their projections [98Kelly JP, Gilbert CD. The projections of different morphological types of ganglion cells in the cat retina J Comp Neurol 1975; 163: 65-80.-01Cohen E, Sterling P. Microcircuitry related to the receptive field center of the on-beta ganglion cell J Neurophysiol 1991; 65: 352-9.]. In the dog, astrocyte density varied according to retinal topography with an increased number around retinal blood vessels and in the peripapillary retina [102Davidson M, Nasisse M, Kornegay J. Intermediate filament complement of the normal and gliotic canine retina J Comp Pathol 1990; 103: 125-34.]. In contrast, astrocyte distribution in the cat retina seemed to be pronounced around the axon bundles of the nerve fiber layer and less intense around blood vessels [103Bussow H. The astrocytes in the retina and optic nerve head of mammals: a special glia for the ganglion cell axons Cell Tissue Res 1980; 206: 367-78.-105Karschin A, Wassle H, Schnitzer J. Shape and distribution of astrocytes in the cat retina Invest Ophthalmol Vis Sci 1986; 27: 828-31.]. Displaced amacrine cells in the dog seem to form a homogenous pattern throughout the retina [106Marroni P, Giannessi E, Coli A. A morphological and morphometrical study of displaced amacrine cells in dog retina Arch Ital Biol 1995; 133: 89-97.]. In the cat, numerous micro-neurons were described in the GCL [107Hughes A, Wieniawa-Narkiewicz E. A newly identified population of presumptive microneurones in the cat retinal ganglion cell layer Nature 1980; 284: 468-70.] exceeding the number of ganglion cells five-fold (730,000 - 850,000 displaced amacrine cells [108Wassle H, Chun MH, Muller F. Amacrine cells in the ganglion cell layer of the cat retina J Comp Neurol 1987; 265: 391-408.,109Wong RO, Hughes A. The morphology, number, and distribution of a large population of confirmed displaced amacrine cells in the adult cat retina J Comp Neurol 1987; 255: 159-77.]) and thus representing some 80% of all neurons in the GCL.

In the primate, the number of retinal ganglion cells is comparable to the human eye (cynomolgus monkey: 900,000 – 1,400,000 ganglion cells [110Furuyoshi N, Furuyoshi M, May CA, Hayreh SS, Alm A, Lütjen-Drecoll E. Vascular and glial changes in the retrolaminar optic nerve in glaucomatous monkey eyes Ophthalmologica 2000; 214: 24-32.], cercopithecus: 1,228,646 ganglion cells [111Herbin M, Boire D, Ptito M. Size and distribution of retinal ganglion cells in the St.Kitts green monkey (Cercopithecus aethiops sabeus) J Comp Neurol 1997; 383: 459-72.], rhesus monkey: 1,500,000 ganglion cells [112Kim CB, Tom BW, Spear PD. Effects of aging on the densities, numbers, and sizes of retinal ganglion cells in rhesus monkey Neurobiol Aging 1996; 17: 431-8.], cebus monkey: 1,340,000 – 1,400,000 ganglion cells [113Silveira LC, Picanco-Diniz CW, Sampaio LF, Oswaldo-Cruz E. Retinal ganglion cell distribution in the cebus monkey a comparison with the cortical magnification factors Vision Res 1989; 29: 1471-83.], human: 700,000 – 1,500,000 ganglion cells [114Curcio CA, Allen KA. Topography of ganglion cells in human retina J Comp Neurol 1990; 300: 5-25.]). Displaced amacrine cells in the GCL show a distinct distribution pattern representing 5-50% of the neurons in the different regions [115Wassle H, Grunert U, Rohrenbeck J, Boycott BB. Retinal ganglion cell density and cortical magnification factor in the primate Vision Res 1990; 30: 1897-911.]: in the fovea region (-3mm), the number of displaced amacrines is at the lower end (5% of all neurons), whereas more nasally the amount raises up to 30% and temporally up to 50%. The estimations for the human retina are 3% displaced amacrines in the fovea region and up to 80% of displaced amacrines in the peripheral retina [114Curcio CA, Allen KA. Topography of ganglion cells in human retina J Comp Neurol 1990; 300: 5-25.].

VII. CONCLUSIONS

Several implications can be drawn for the different animal models used in glaucoma research that should be kept in mind when using these species.

The mouse seems to be a good comparative animal model to study the influence of the LC on the process of glaucomatous optic nerve head changes. Since it lacks a LC, the mouse can not be used for LC specific investigations; in addition, the size of the eye leads to different physical and physiological conditions which limit the transfer to the human situation. Strain differences seem to play a crucial role when comparing quantitative data of the optic nerve and retina of different mouse strains. The composition of the optic nerve head is comparable to the human situation (only non-myelinated axons and astrocytes) although the blood supply shows clear differences.

In the rat, strain differences seem to play an important role when investigating the role of the LC. So far, there exist no quantitative studies comparing the LC in different rat strains but the findings in the literature imply differences in susceptibility to elevated pressure between different strains. Such studies could also clarify the role of the LC and its composition on the process of glaucoma. In rat as in mouse, the vascular supply and the localization of the central retinal vessels should be taken into account when comparing findings with the human situation.

The rabbit, chicken and quail seem to be less useful models to study the pathogenic process of glaucoma. The major problem comprises the myelinization of the axons penetrating through the sparsely developed LC into the nerve fiber layer of the retina changing profoundly the situation of cell composition and mechanical reactivity in the optic nerve head region. In addition, the retina is avascular which probably has a major influence on the optic nerve head blood supply, too.

Due to the size and anatomy of the optic nerve head and inner retina, the pig eye has numerous advantages compared to the animals discussed so far. It contains a well-developed lamina cribrosa (as do cat and dog), and the number of retinal ganglion cells is fairly high. The pig has only a poorly developed area centralis, but the possible influence of the fine retinal structure on glaucoma pathology has not yet been evaluated. In contrast to the porcine anatomy, the dog and cat eyes show relatively low values of retinal ganglion cell numbers although the centralization of the retina is more developed showing a clear area centralis. One major advantage to use cat eyes in glaucoma research is the well established classification of retinal ganglion cells. On the other hand, cats (as dogs) have an elaborated tapetum lucidum, which possible might cause trouble when comparing electrophysiological data in vivo.

The latter restriction holds also true for the primate monkey eye which shows closest relation to the human anatomy. This might be especially of interest when discussing the role of vascular disturbances and their possible role for the onset and progress of glaucoma.

VIII. SUPPLEMENT: VARIETY OF CURRENT GLAUCOMA MODELS

Rodents. Numerous different glaucoma models exist in the mouse and rat eye comprising almost all aspects of mutations (natural and induced) and manipulations (blood flow changes, intravitreal injections, optic nerve injury). All models were described recently in an excessive review [116Pang IH, Clark AF. Rodent models for glaucoma retinopathy and optic neuropathy J Glaucoma 2007; 16: 483-505.].

Rabbit. Corticosteroid-induced ocular hypertension. Intraocular alpha-chymotrypsin injection. Short time intraocular pressure elevation by needle injection.

Pig. Episcleral vein cauterization. In vitro models with porcine cadaver eyes (e.g. anterior chamber perfusion).

Dog. POAG in Beagles, American Cocker Spaniels, and other races. Spontaneous secondary glaucoma.

Cat. Primary and secondary narrow angle/ angle closure glaucoma in different cat strains. Short time intraocular pressure elevation by needle injection. Corticosteroid-induced ocular hypertension.

Monkey. A small colony exists with an incidence of natural occurring glaucoma. Manipulations include laser treatment of the trabecular meshwork and damage of the optic nerve.

Chicken. Light-induced glaucoma.

Quail. Natural occurring glaucomatous mutant in the Japanese albino quail.

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Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

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Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

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Alessandro Laviano
(Sapienza - University of Rome, Italy)

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Philippe Hernigou
(Paris University, France)

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Peter Chiba
(University of Vienna, Austria)

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(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
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Kenji Hashimoto
(Chiba University, Japan)

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(Chinese University of Hong Kong, Hong Kong)

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(National Central University, Taiwan)


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