Remodeling of second-order neurons in the retina of rd/rd mutant mice

Strettoi, Enrica; Pignatelli, Vincenzo; Rossi, Chiara; Porciatti, Vittorio; Falsini, Benedetto

doi:10.1016/s0042-6989(02)00594-1

Cited by 201 publications

(205 citation statements)

References 42 publications

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“…In addition, in both cell types, irregular processes extending to the ONL were observed. Similar morphological alterations have been found in other mouse models lacking functional cones and/or rods (Strettoi et al, 2003;Claes et al, 2004). Together, these findings strongly suggest that rod photoreceptor inputs are required for the functional maintenance of synaptic contacts.…”

Section: Discussionsupporting

confidence: 84%

Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1

Hüttl¹,

Michalakis²,

Seeliger³

et al. 2005

J. Neurosci.

146

134

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Cyclic nucleotide-gated (CNG) channels are important mediators in the transduction pathways of rod and cone photoreceptors. Native CNG channels are heterotetramers composed of homologous A and B subunits. In heterologous expression systems, B subunits alone cannot form functional CNG channels, but they confer a number of channel properties when coexpressed with A subunits. To investigate the importance of the CNGB subunits in vivo, we deleted the CNGB1 gene in mice. In the absence of CNGB1, only trace amounts of the CNGA1 subunit were found on the rod outer segment. As a consequence, the vast majority of isolated rod photoreceptors in mice lacking CNGB1 (CNGB1 Ϫ/Ϫ ) failed to respond to light. In electroretinograms (ERGs), CNGB1 Ϫ/Ϫ mice showed no rod-mediated responses. The rods also showed a slow-progressing degeneration caused by apoptotic death and concurred by retinal gliosis. Cones were primarily unaffected and showed normal ERG responses up to 6 months, but they started to degenerate in later stages. At the age of ϳ1 year, CNGB1 Ϫ/Ϫ animals were devoid of both rods and cones. Our results show that CNGB1 is a crucial determinant of native CNG channel targeting. As a result of the lack of rod CNG channels, CNGB1 Ϫ/Ϫ mice develop a retinal degeneration that resembles human retinitis pigmentosa.

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Section: Discussionsupporting

confidence: 84%

Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1

Hüttl¹,

Michalakis²,

Seeliger³

et al. 2005

J. Neurosci.

146

134

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“…In addition to direct effects on photoreceptors, the rd͞rd mutation also results in alterations in inner retinal circuitry (32)(33)(34). Similar changes have also been reported in retinas of mice with mutations in the Leber's congenital amaurosis-causing gene Crx (35) and after simple visual deprivation (36,37).…”

Section: Pharmacologic Inhibition Of Visual Retinoid Cycle Causes Lossupporting

confidence: 61%

Inner retinal photoreception independent of the visual retinoid cycle

Tu¹,

Owens²,

Anderson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Mice lacking the visual cycle enzymes RPE65 or lecithin-retinol acyl transferase (Lrat) have pupillary light responses (PLR) that are less sensitive than those of mice with outer retinal degeneration (rd͞rd or rdta). Inner retinal photoresponses are mediated by melanopsinexpressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat. To test this hypothesis, we generated rpe65 ؊/؊ ; rdta and lrat ؊/؊ ; rd͞rd mutant mice. Unexpectedly, both rpe65 ؊/؊ ; rdta and lrat ؊/؊ ; rd͞rd mice demonstrate paradoxically increased PLR photosensitivity compared with mice mutant in visual cycle enzymes alone. Acute pharmacologic inhibition of the visual cycle of melanopsin-deficient mice with all-trans-retinylamine results in a near-total loss of PLR sensitivity, whereas treatment of rd͞rd mice has no effect, demonstrating that the inner retina does not require the visual cycle. Treatment of rpe65 ؊/؊ ; rdta with 9-cis-retinal partially restores PLR sensitivity. Photic sensitivity in P8 rpe65 ؊/؊ and lrat ؊/؊ ipRGCs is intact as measured by ex vivo multielectrode array recording. These results demonstrate that the melanopsin-dependent ipRGC photocycle is independent of the visual retinoid cycle.melanopsin ͉ pupillary light response ͉ retinal degeneration ͉ retinal ganglion cell ͉ visual photocycle M ice blind from outer retinal degeneration retain the ability to entrain their circadian rhythms to external light-dark cycles, have active pupillary light responses (PLRs), and exhibit photically induced melatonin suppression (1-4). These responses depend on the opsin family member melanopsin (5), which is expressed exclusively in a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) (6-8). Mice with nonfunctional or degenerated rods and cones that also lack melanopsin show no photically influenced behavior or physiology (9, 10), and intrinsic photosensitivity of retinal ganglion cells is lost in the absence of melanopsin (9,11,12). Melanopsin forms a functional photopigment when heterologously expressed in COS cells (13), Xenopus oocytes (14), Neuro-2A cells (15), or HEK-293 cells (16). Melanopsin is thus necessary for ipRGC photoreception, and is sufficient to confer photosensitivity on intrinsically insensitive cell types. Taken together, these results strongly suggest that melanopsin is the photopigment of inner retinal photoreception.All opsin photopigments use a retinoid chromophore that undergoes isomerization upon absorption of an appropriate wavelength photon. In rod photoreceptors, 11-cis-retinal chromophore is photoisomerized to all-trans-retinal which dissociates from the opsin protein (17). This all-trans-retinal photoproduct is recycled to the active (11-cis) form by enzymatic conversion in the adjacent retinal pigment epithelium (RPE) (18). The chromophore used by melanopsin in situ is not presently known. ipRGCs are physically distant from the enzymatic chromophore regeneration machinery of the RPE. It is present...

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“…Linberg et al from the OPL has also been reported in the rd degeneratioñ Strettoi & Pignatelli, 2000;Strettoi et al, 2003;Gouras & Tanabe, 2003! which provides another point of contrast to the responses after retinal detachment where rod bipolar cells and horizontal cells rapidly sprout neurites that grow into the ONL and even into the subretinal space~Lewis et al, 1998!.…”

Section: Discussionmentioning

confidence: 85%

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

Fariss

Heckenlively

Farber³

et al. 2005

Vis Neurosci

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Retinal development in 3 strains of rd-3/rd-3 mutant mice, previously shown to have different rates of degeneration, was studied using light, electron, and immunofluorescence microscopy. The time course and phenotype of the degeneration as well as details on the mechanism of massive photoreceptor cell loss are compared with other known retinal degenerations in mice. Up until postnatal day (P) 10, the retinas of all three strains (RBF, 4Bnr, In-30) develop similarly to those of pigmented and nonpigmented controls. TUNEL-positive cells appear in the outer nuclear layer (ONL) by P14, and reach a maximum in all three mutant strains around P21. Scattered rods and cones form a loose, monolayered ONL by 8 weeks in the albino RBF strain, by 10 weeks in the albino 4Bnr strain, and by 16 weeks in the pigmented In-30 strain. Though the initial degeneration begins in the central retina, there is no preferred gradient of cell death between central and peripheral photoreceptors. Rods and cones are present at all ages examined. During development, stacks of outer segments (OS) form in all three strains though they never achieve full adult lengths, and often have disorganized, atypical OS. Rod opsin is expressed in the developing OS but is redistributed into plasma membrane as OS degeneration proceeds. Retinal pigment epithelial (RPE) cells of all mutant strains contain packets of phagocytosed OS, and their apical processes associate with the distal ends of the OS. At their synaptic sites, photoreceptor terminals contain ribbons apposed to apparently normal postsynaptic triads. As photoreceptors are lost, Müller cells fill in space in the ONL but they do not appear to undergo significant hypertrophy or migration, though during the degeneration, glial fibrillary acidic protein (GFAP) expression is gradually upregulated. Macrophage-like cells are found frequently in the subretinal space after the onset of photoreceptor apoptosis. As OS disappear, the RPE apical processes revert to simple microvilli. Late in the degeneration, some RPE cells die and neighboring cells appear to flatten as if to maintain confluence. In regions of RPE cell loss that happen to lie above retina where the ONL is gone, cells of the inner nuclear layer (INL), wrapped by Müller cell processes, may front directly on Bruch's membrane.

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Remodeling of second-order neurons in the retina of rd/rd mutant mice

Cited by 201 publications

References 42 publications

Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1

Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1

Inner retinal photoreception independent of the visual retinoid cycle

Morphological characterization of the retinal degeneration in three strains of mice carrying the rd-3 mutation

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