Effects of ocular hypertension in the visual system of pigmented mice.

Francisco J Valiente-Soriano,Manuel Salinas-Navarro,Arturo Ortín-Martínez,Manuel Vidal-Sanz,Marcelino Avilés-Trigueros,Marta Agudo-Barriuso,Manuel Jiménez-López,María P Villegas-Pérez,José M Bernal-Garro,Luis Alarcón-Martínez,Tudor C Badea

doi:10.1371/journal.pone.0121134

Abstract

To study the effects of ocular hypertension (OHT) on the visual system of C57BL/6 pigmented mice, the limbal and episcleral veins of the left eye were laser photocoagulated (LP). LP increased the intraocular pressure during the first five days (d), reaching basal values at 7d. To investigate the effect of OHT on the retinal ganglion cell (RGC) retrograde axonal transport, hydroxistilbamidine methanesulfonate (OHSt) was applied to both superior colliculi (SCi) and the retinas were dissected 2 or 4 weeks after LP. To determine RGC survival, these same retinas were immunoreacted against Brn3a (general RGC population) and melanopsin (intrinsically photosensitive RGCs, m+RGCs). To study whether OHT affected non-RGC neurons in the ganglion cell layer (GCL), RGCs were immunodetected with Brn3a and all GCL nuclei counterstained with DAPI in a group of animals examined 4 weeks post-LP. Innervation of the SCi was examined at 10 days, 8 or 14 weeks after LP with the orthogradely transported cholera toxin subunit-B. OHT resulted in diffuse and sectorial loss of OHSt+RGCs (50% at 2 weeks and 62% at 4 weeks) and in a comparable loss of Brn3a+RGCs at the same time intervals. m+RGCs decreased to 59% at 2 weeks and to 46% at 4 weeks, such loss was diffuse, did not parallel the sectorial loss of the general RGC population and was more severe in the superior-temporal retina. In the GCL, cell loss is selective for RGCs and does not affect other non-RGC neurons. The retinotectal innervation appeared significantly reduced at 10 days (55.7%) and did not progress further up to 14 weeks (46.6%). Thus, LP-induced OHT results in retrograde degeneration of RGCs and m+RGCs, as well as in the loss of CTB-labelled retinotectal terminals.

Highlights

Glaucomatous optic neuropathies (GON) are a leading cause of blindness in the developed countries
Because experimental glaucoma has been shown to affect the circadian timing system [37,38] and several reports claim that intrinsic photosensitive retinal ganglion cells or melanopsin-expressing RGCs (m+RGCs) survive better after ocular hypertension (OHT) in rats [39,40] whereas other reports indicate the contrary for mice [41] and rats [37,42,43], we have investigated the effects of OHT in the population of m+RGCs
Their distribution is not homogeneous, rather their density is higher in the medial than in the peripheral retina (Fig. 2A', B') and their total numbers are comparable to those previously reported for pigmented mice [49,51] m+RGCs are found throughout the retina, they are more abundant in the hemi- temporal and dorsal retina (Fig. 2C-C')

Summary

Introduction

Glaucomatous optic neuropathies (GON) are a leading cause of blindness in the developed countries. One of the most important risk factors in GON is ocular hypertension (OHT), probably the only risk factor for which there are current therapeutic approaches [1]. OHT-Effects in Pigmented Mice Visual System experimental models to induce and study ocular hypertension in adult mice such as: the episcleral vein occlusion [4] or the injection of polystyrene microbeads into the anterior chamber [5,6,7]. One of the most popular models involves laser cauterization of the episcleral and perilimbal veins in adult albino rats [16,17,18,19,20,21]. There are several reports in adult albino [22,23,24,25,26,27,28] or pigmented [29,30,31,32,33,34,35,36] mice

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Conclusion