Altered glial gene expression, density, and architecture in the visual cortex upon retinal degeneration.

Genes encoding the proteins of cytoskeletal intermediate filaments (IF) are tightly regulated, and they are important for establishing neural connections. However, it remains uncertain to what extent neurological disease alters IF gene expression or impacts cells that express IFs. In this study, we determined the onset of visual deficits in a mouse model of progressive retinal degeneration (Pde6b(-) mice; Pde6b(+) mice have normal vision) by observing murine responses to a visual task throughout development, from postnatal day (PND) 21 to adult (N=174 reliable observations). Using Q-PCR, we evaluated whether expression of the genes encoding two Type III IF proteins, glial fibrillary acidic protein (GFAP) and vimentin was altered in the visual cortex before, during, and after the onset of visual deficits. Using immunohistochemical techniques, we investigated the impact of vision loss on the density and morphology of astrocytes that expressed GFAP and vimentin in the visual cortex. We found that Pde6b(-) mice displayed 1) evidence of blindness at PND 49, with visual deficits detected at PND 35, 2) reduced GFAP mRNA expression in the visual cortex between PND 28 and PND 49, and 3) an increased ratio of vimentin:GFAP-labeled astrocytes at PND 49 with reduced GFAP cell body area. Together, these findings demonstrate that retinal degeneration modifies cellular and molecular indices of glial plasticity in a visual system with drastically reduced visual input. The functional consequences of these structural changes remain uncertain.

Effects of age and retinal degeneration on the expression of proprotein convertases in the visual cortex.

Proprotein convertases (PCs) comprise a large family of subtilisin-like, eukaryotic, serine endoproteases that process substrates important in the development, homeostasis, and pathology of the nervous system. Despite important interactions with these substrates, including neurotrophins, PC expression throughout normal postnatal development and disease progression in the brain remains unknown. The primary objective of this study was to determine whether the expression profiles of widely expressed and tissue-specific PCs varied during normal brain development or neurological disorders. We examined the expression of mRNAs for seven PCs in the visual cortex of normal and visually impaired mice at 10 postnatal developmental time points between Week 1 and Week 35. Widely expressed PCs (furin, PACE4, PC5, and PC7) all exhibited a similar expression profile. High mRNA levels were seen at Week 1 with levels generally lower over the next 5-6 weeks. In visually impaired mice, widely expressed PCs again all exhibited a similar expression profile, but it was dramatically different than observed in normal mice. The temporal expression of tissue-specific PCs varied in wild-type mice. Interestingly, this variability was sharply reduced in visually impaired mice. Overall, these data suggest a timetable of altered PC expression that corresponds closely with the formation of functional visual maps in the visual cortex. The implications of these findings are discussed in the context of neurotrophin processing and synaptogenesis in the developing visual cortex.