title: Assessment of inner retina dysfunction and progressive ganglion cell loss in a mouse model of glaucoma.
abstract: The DBA/2J mouse is a model of ocular hypertension and retinal ganglion cell (RGC) degeneration, the main features of which are iris pigment dispersion (IPD) and iris stromal atrophy (ISA). These animals also experience glaucomatous changes, including an increase in intraocular pressure (IOP) beginning at about 9-12 months of age and sectorial RGC death in the retina. The aim of this study was to determine the onset of functional changes exhibited by DBA/2J mice in the inner retina. This was performed by means of electroretinographic recordings (scotopic threshold response, STR) and their correlation with morphological changes (loss of RGCs). To this end, we recorded the scotopic threshold response in control C57BL/6J and in DBA/2J mice at different ages. The RGCs, in both DBA/2J and C57BL/6J animals, were identified at 15 months of age by retrograde tracing with an analogue of fluorogold, hydroxystilbamidine methanesulfonate (OHSt), applied on the superior colliculi. Whole mount retinas were processed to quantify the population of RGCs identified by fluorogold tracing and Brn3a immunodetection, and were counted using image analysis software; an isodensity contour plot was generated for each retina. DBA/2J mice showed a significant reduction in the positive STR (pSTR) amplitudes at 12 months of age, as compared to control C57BL/6J mice of the same age. The pSTR mean amplitude decreased to approximately 27.82% of the values recorded in control mice (p = 0.0058). STR responses decreased in both strains as a result of the natural process of aging, but the decrease was more pronounced in DBA/2J mice. Furthermore, quantification of the total number of RGCs identified by OHSt and Brn3a expression showed a reduced population of RGCs in DBA/2J mice as compared to control mice. Regression analysis revealed significant correlations between the decrease in pSTR and a non-homogeneous reduction in the number of RGCs throughout the retina. Our results indicate the existence of a correlation between retinal function impairment and RGC loss. This functional and morphological analysis allows a reliable assessment of the progression of the disease.
authors.affiliation: Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Complutense University of Madrid, c/Arcos de Jalón 118, E-28037 Madrid, Spain; Red Española Temática de Investigación Cooperativa en Patología Ocular Prevalente y Crónica, Instituto de Salud Carlos III, Madrid, PC, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Pérez de Lara
authors.affiliation: Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Complutense University of Madrid, c/Arcos de Jalón 118, E-28037 Madrid, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Santano
authors.affiliation: Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Complutense University of Madrid, c/Arcos de Jalón 118, E-28037 Madrid, Spain; Red Española Temática de Investigación Cooperativa en Patología Ocular Prevalente y Crónica, Instituto de Salud Carlos III, Madrid, PC, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Guzmán-Aránguez
authors.affiliation: Experimental Ophthalmology Laboratory, Dept. of Ophthalmology, College of Medicine, University of Murcia, Regional Campus of International Excellence "Campus Mare Nostrum", Murcia Institute of Bio-Health Research (IMIB), E-30100 Murcia, Spain; Red Española Temática de Investigación Cooperativa en Patología Ocular Prevalente y Crónica, Instituto de Salud Carlos III, Madrid, PC, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Valiente-Soriano
authors.affiliation: Experimental Ophthalmology Laboratory, Dept. of Ophthalmology, College of Medicine, University of Murcia, Regional Campus of International Excellence "Campus Mare Nostrum", Murcia Institute of Bio-Health Research (IMIB), E-30100 Murcia, Spain; Red Española Temática de Investigación Cooperativa en Patología Ocular Prevalente y Crónica, Instituto de Salud Carlos III, Madrid, PC, Spain.
authors.forename: Marcelino
authors.initials: M
authors.lastname: Avilés-Trigueros
authors.affiliation: Experimental Ophthalmology Laboratory, Dept. of Ophthalmology, College of Medicine, University of Murcia, Regional Campus of International Excellence "Campus Mare Nostrum", Murcia Institute of Bio-Health Research (IMIB), E-30100 Murcia, Spain; Red Española Temática de Investigación Cooperativa en Patología Ocular Prevalente y Crónica, Instituto de Salud Carlos III, Madrid, PC, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vidal-Sanz
authors.affiliation: Department of Systems Biology, University of Alcalá, 28871 Alcalá de Henares, Spain; Red Española Temática de Investigación Cooperativa en Patología Ocular Prevalente y Crónica, Instituto de Salud Carlos III, Madrid, PC, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: de la Villa
authors.affiliation: Department of Biochemistry and Molecular Biology IV, Faculty of Optics and Optometry, Complutense University of Madrid, c/Arcos de Jalón 118, E-28037 Madrid, Spain; Red Española Temática de Investigación Cooperativa en Patología Ocular Prevalente y Crónica, Instituto de Salud Carlos III, Madrid, PC, Spain. Electronic address: jpintor@ucm.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Pintor
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D002452:Cell Count; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D060005:Genotyping Techniques; D005901:Glaucoma / Q000503:physiopathology*; D007429:Intraocular Pressure / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008856:Microscopy, Fluorescence; D009410:Nerve Degeneration / Q000503:physiopathology; D055254:Night Vision; D009901:Optic Nerve Diseases / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D012160:Retina / Q000503:physiopathology*; D012162:Retinal Degeneration / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000473:pathology*; D014065:Tonometry, Ocular; D014792:Visual Acuity / Q000502:physiology
keywords: DBA/2J; electroretinogram (ERG); fluorogold; neuronal degeneration; retina; retinal ganglion cells (RGC); scotopic threshold response (STR)