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.
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.
Authors: Yolandi van der Merwe; Matthew C Murphy; Jeffrey R Sims; Muneeb A Faiq; Xiao-Ling Yang; Leon C Ho; Ian P Conner; Yu Yu; Christopher K Leung; Gadi Wollstein; Joel S Schuman; Kevin C Chan Journal: Neurotherapeutics Date: 2021-04-13 Impact factor: 7.620
Authors: Francisco J Valiente-Soriano; Manuel Salinas-Navarro; Manuel Jiménez-López; Luis Alarcón-Martínez; Arturo Ortín-Martínez; José M Bernal-Garro; Marcelino Avilés-Trigueros; Marta Agudo-Barriuso; María P Villegas-Pérez; Manuel Vidal-Sanz Journal: PLoS One Date: 2015-03-26 Impact factor: 3.240
Authors: Manuel Vidal-Sanz; Caridad Galindo-Romero; Francisco J Valiente-Soriano; Francisco M Nadal-Nicolás; Arturo Ortin-Martinez; Giuseppe Rovere; Manuel Salinas-Navarro; Fernando Lucas-Ruiz; Maria C Sanchez-Migallon; Paloma Sobrado-Calvo; Marcelino Aviles-Trigueros; María P Villegas-Pérez; Marta Agudo-Barriuso Journal: Front Neurosci Date: 2017-04-26 Impact factor: 4.677
Authors: Marina Martínez-Carmona; Fernando Lucas-Ruiz; Alejandro Gallego-Ortega; Caridad Galindo-Romero; María Norte-Muñoz; María José González-Riquelme; Francisco J Valiente-Soriano; Manuel Vidal-Sanz; Marta Agudo-Barriuso Journal: Int J Mol Sci Date: 2021-12-21 Impact factor: 5.923
Authors: Eline Dekeyster; Emiel Geeraerts; Tom Buyens; Chris Van den Haute; Veerle Baekelandt; Lies De Groef; Manuel Salinas-Navarro; Lieve Moons Journal: PLoS One Date: 2015-11-11 Impact factor: 3.240