title: Retinal neurodegenerative changes in the adult insulin receptor substrate-2 deficient mouse.
abstract: Insulin receptor substrate-2 (Irs2) mediates peripheral insulin action and is essential for retinal health. Previous investigations have reported severe photoreceptor degeneration and abnormal visual function in Irs2-deficient mice. However, molecular changes in the Irs2(-)(/)(-) mouse retina have not been described. In this study, we examined retinal degenerative changes in neuronal and glial cells of adult (9- and 12-week old) Irs2(-)(/)(-) mice by immunohistochemistry. 9-week old Irs2(-)(/)(-) mice showed significant thinning of outer retinal layers, concomitant to Müller and microglial cell activation. Photoreceptor cells displayed different signs of degeneration, such as outer/inner segment atrophy, redistribution of rod- and cone-opsins and spatial disorganization of cone cells. This was accompanied by synaptic changes at the outer plexiform layer, including the retraction of rod-spherules, reduction of photoreceptor synaptic ribbons and synaptic remodeling in second order neurons (i.e. loss and sprouting of dendritic processes in rod bipolar and horizontal cells). By 12 weeks of age, the thickness of inner retinal layers was severely affected. Although inner plexiform layer stratification remained unchanged at this stage, rod bipolar cell axon terminals were significantly depleted. Significant loss of Brn3a(+) retinal ganglion cells occurred in 12-week old Irs2(-)(/)(-) mice, in contrast to younger ages. Adult Irs2(-)(/)(-) mice showed clear hallmarks of neurodegeneration and disruption of the inner retina with increasing age. Pharmacological stimulation of Irs2 signaling pathway may provide additional neuroprotection in certain degenerative retinopathies.
authors.affiliation: Ophthalmic Research Unit "Santiago Grisolia", Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Mara
authors.initials: M
authors.lastname: Albert-Fort
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK. Electronic address: j.romero@qub.ac.uk.
authors.forename: José R
authors.initials: JR
authors.lastname: Hombrebueno
authors.affiliation: Ophthalmic Research Unit "Santiago Grisolia", Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Sheila
authors.initials: S
authors.lastname: Pons-Vazquez
authors.affiliation: Molecular Neuroendocrinology Department of Research Center Principe Felipe, Valencia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sanz-Gonzalez
authors.affiliation: Surgery-Ophthalmology Department, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Diaz-Llopis
authors.affiliation: Ophthalmic Research Unit "Santiago Grisolia", Faculty of Medicine, University of Valencia, Valencia, Spain; Surgery-Ophthalmology Department, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Pinazo-Durán
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004596:Electroretinography; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000473:pathology*; D051245:Retinal Bipolar Cells / Q000378:metabolism / Q000473:pathology*; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D014785:Vision, Ocular / Q000502:physiology*
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse
keywords: Irs2; immunohistochemistry; microglia; neuroprotection; reactive gliosis; retina; retinal degeneration; synaptic plasticity