Ocular Hypertension Results in Retinotopic Alterations in the Visual Cortex of Adult Mice

Abstract

Purpose: Glaucoma is a group of optic neuropathies characterized by the loss of retinal ganglion cells (RGCs). Since ocular hypertension (OHT) is a main risk factor, current therapies are predominantly based on lowering eye pressure. However, a subset of treated patients continues to lose vision. More research into pathological mechanisms underlying glaucoma is therefore warranted in order to develop novel therapeutic strategies. In this study we investigated the impact of OHT from eye to brain in mice.

Methods: Monocular hypertension (mOHT) was induced in CD-1 mice by laser photocoagulation (LP) of the perilimbal and episcleral veins. The impact on the retina and its main direct target area, the superficial superior colliculus (sSC), was examined via immunostainings for Brn3a, VGluT2 and GFAP. Alterations in neuronal activity in V1 and extrastriate areas V2L and V2M were assessed using in situ hybridization for the activity reporter gene zif268.

Results: Transient mOHT resulted in diffuse and sectorial RGC degeneration. In the sSC contralateral to the OHT eye, a decrease in VGluT2 immunopositive synaptic connections was detected one week post LP, which appeared to be retinotopically linked to the sectorial RGC degeneration patterns. In parallel, hypoactivity was discerned in contralateral retinotopic projection zones in V1 and V2. Despite complete cortical reactivation 4 weeks post LP, in the sSC no evidence for recovery of RGC synapse density was found and also the concomitant inflammation was not completely resolved. Nevertheless, sSC neurons appeared healthy upon histological inspection and subsequent analysis of cell density revealed no differences between the ipsi- and contralateral sSC.

Conclusion: In addition to RGC death, OHT induces loss of synaptic connections and neuronal activity in the visual pathway and is accompanied by an extensive immune response. Our findings stress the importance of looking beyond the eye and including the whole visual system in glaucoma research.

• Glaucoma
• ocular hypertension
• retinal ganglion cell
• superior colliculus
• visual cortex

Acknowledgments

The authors thank Ria Vanlaer, Lut Noterdaeme and Marijke Christiaens for their technical assistance.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Eline Dekeyster is supported by a PhD fellowship of the Research Foundation Flanders (FWO). Jeroen Aerts is supported by a PhD fellowship of the Agency for Innovation through Science and Technology Flanders (IWT Vlaanderen). This study was also supported by the Flemisch Institute for the Promotion of Scientific Research (IWT) [SBO Optobrain 110086], the Research Foundation Flanders (FWO) [G.0A65.13], a type I Hercules Equipment grant [AKUL/09/038], national grants from the Research Council of KU Leuven [OT10/033] and a research grant from the Ministry of Economy and Competitiveness of Spain [SAF2012-38328].