Yves Sauvé

University of Alberta, Edmonton, Alberta, Canada

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Publications (74)261.89 Total impact

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    ABSTRACT: PURPOSE. Recording oscillatory potentials (OPs) to document how age impacts on rod- and cone-driven inner retina function. METHODS. Dark- and light-adapted electroretinogram (ERG) luminance-response functions were recorded in healthy human subjects aged 20-39, 40-59, and 60-82 years. Raw ERG traces (0.1-300Hz) were filtered (75-300Hz) to measure OPs trough-to-peak in the time-amplitude domain. Morlet wavelet transform (MWT) allowed documenting OPs time-amplitude-frequency distribution from raw traces. RESULTS. Under dark adaptation, both methods revealed reduced OP amplitudes and prolonged implicit times by 40 years of age. MWT identified a high-frequency band as the main oscillator, which frequency (150-155Hz) was unaffected by age. Under light adaptation, most OP peaks were delayed by 40 years of age. Peak-trough measures yielded inconsistent results in relation to luminance. Contrastingly, MWT distinguished two frequency bands at all luminances: high frequency (135 ± 6Hz) time locked to the onset of early OPs and low frequency (82 ± 7Hz), giving rise to early and late OPs. By 60 years, there was a consistent power reduction specific to the low-frequency band. CONCLUSION. Age-related OP changes precede those seen with a- (photoreceptoral) and b-waves (post-photoreceptoral). In addition, MWT allows quantifying distinct low- and high-frequency oscillators in the human retina, which complement traditional OP analysis methods. The identification of an age-independent OP marker (light-adapted high frequency band) opens a new dimension for the screening of retinal degenrations and their impact on inner retina function.
    Investigative ophthalmology & visual science. 07/2014;
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    ABSTRACT: We sought to study the expression pattern of Disabled-1 (Dab1; an adaptor protein in the reelin pathway) in the cone-rich retina of a diurnal murine rodent. Expression was examined by western blotting and immunohistochemistry using well-established antibodies against Dab1 and various markers of retinal neurons. Western blots revealed the presence of Dab1 (80 kDa) in brain and retina of the Nile grass rat. Retinal immunoreactivity was predominant in soma and dendrites of horizontal cells as well as in amacrine cell bodies aligned at the INL/IPL border. Dab1(+) neurons in the inner retina do not stain for parvalbumin, calbindin, protein kinase C-alpha, choline acetyltransferase, glutamic acid decarboxylase, or tyrosine hydroxylase. They express, however, the glycine transporter GlyT1. They have small ovoid cell bodies (7.1±1.06 μm in diameter) and bistratified terminal plexii in laminas a and b of the IPL. Dab1(+) amacrine cells are evenly distributed across the retina (2600 cells/mm(2)) in a fairly regular mosaic (regularity indexes ≈3.3-5.5). We conclude that retinal Dab1 in the adult Nile grass rat exhibits a dual cell patterning similar to that found in human. It is expressed in horizontal cells as well as in a subpopulation of glycinergic amacrine cells undetectable with antibodies against calcium-binding proteins. These amacrine cells are likely of the AII type.
    Experimental Eye Research 06/2014; · 3.03 Impact Factor
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    ABSTRACT: The aim of this pilot study was to test the effectiveness of a light therapy device (the Luminette®) on the delayed sleep phase syndrome (DSPS) in a group of adolescents (n = 10) between 15 and 18 years old (three girls and seven boys, average age 16.3 years old) affected by this syndrome. This study was conducted using an experimental single blind placebo-controlled design. The diagnosis of the DSPS among participants was established based on the criteria specified in the International Classification of Sleep Disorders – Second Edition (ICSD-2). The data were collected using two questionnaires: (1) Teen Sleep Diary (TSD) and (2) the Pediatric Daytime Sleepiness Scale (PDSS). The results indicated significant improvements in the experimental group (users of the real Luminette®) compared to the control group (users of the placebo Luminette®) with respect to the delay of sleep onset, the quality and the daytime sleepiness. This study underlines the importance of conducting further research on the Luminette® with a larger sample of adolescents with DSPS.
    Médecine du Sommeil 04/2014;
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    ABSTRACT: PURPOSE. To examine the pattern of cone degeneration in the retina of a transgenic mouse model of STGD3. METHODS. Investigations were performed on ELOVL4/TG1-2 transgenic (TG) mice and wild-type (WT) littermates from one to 24 months of age. Phenotypes were assessed by fundus imaging, fatty acid analysis and ERG recording. Cone degeneration pattern was determined on retina wholemounts using immunohistochemistry and Voronoi domain analyses. RESULTS. Consistent with low transgene expression, photoreceptors degenerate very slowly. At one month, anatomical structure and fatty acid composition of the TG retina is comparable to WT. Rod loss appears at 2 months, exhibiting a central to peripheral gradient, and fundus defects are observed at 3 months. In contrast, cone morphology, distribution and function are still normal at 12 months. Cone loss becomes apparent at 15 months when the outer nuclear layer is reduced to 3-4 photoreceptor rows. This process starts at the center of the retina and affects cone subtypes similarly. Very few cones remain at 24 months, after all rods have disappeared (18 months). Quantitative studies focusing on cones expressing M-opsin show a net increase in Voronoi domains and a significant decrease in regularity indexes only beyond 15 months. CONCLUSION. Photoreceptor degeneration in this STGD3 mouse model follows the time course of a slow rod-cone dystrophy. The cone mosaic is preserved for almost one year after the onset of rod loss. This long delay provides an opportunity to examine rod-cone interactions during retinal degeneration and to test therapeutic effectiveness at protracting cone dysfunction.
    Investigative ophthalmology & visual science 12/2013; · 3.43 Impact Factor
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    ABSTRACT: Purpose The P23H rhodopsin mutation is an extensively studied model of ADRP. We evaluated the anatomical changes using SD-OCT and correlate the findings and retinal thickness values with immunocytochemistry. Functional changes were analyzed Methods Heterozygous P23H pigmented transgenic rats aged from P18 to P180 were studied. LE rats bred with Sprague Dawley (SD) 1 month old served as wild type controls. Visual acuity and contrast sensitivity evaluation was performed every month. Corneal ERGs were recorded under scotopic and photopic conditions. Retinal thicknesses at different levels (total thickness, ONL + RPE, ONL and IPL), fundus autofluorescence (FAF) and fluorescein angiography was performed in 3 animals at P150 using Spectralis OCT and HRA (Heidelberg Engineering, Germany). Retinas were immunostained for ICC. Results Retinal thicknesses diminution was seen in OCT sections, with a clear loss of ONL and morphological modifications. Statically differences were found between groups in all evaluated thicknesses. In the P23H rats, change in FAF was noted comparing to control group, as sparse autofluorescent dots. No relevant changes were observed in the angiography pattern. ICC showed a progressive decrease in ONL thickness. Functional changes were progressive with time. Conclusion Anatomical changes in pigmented P23H can be observed using SD-OCT and immunocytochemistry, with a good correlation between their values. SD-OCT and FAF are important tools for research in retinal degenerations.
    Acta ophthalmologica 08/2013; 91(s252). · 2.44 Impact Factor
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    ABSTRACT: PURPOSE. To assess the impact of both dry and wet (neovascular) age-related macular degeneration (AMD) on panretinal function. METHODS. Light- and dark-adapted full-field electroretinogram (ERG) recordings were obtained over a 5-log-unit intensity range from both eyes of 25 patients with unilateral wet AMD. Fellow eyes showed various signs of dry AMD ranging from multiple medium-sized drusen to non-central geographic atrophy. The leading edges of rod-isolated ERG a-waves were fitted to a quantitative model of phototransduction. ERG a- and b-wave amplitudes and implicit times were compared between wet and dry AMD eyes and from non-AMD eyes of age-matched subjects. A quantitative and objective assessment of dark adaptation was achieved by recording the recovery of the pure rod b-wave (post-synaptic depolarization of rod bipolar cells); b-wave amplitudes were measured at 120-second intervals for 20 min. and normalized to the amplitude recorded at t=20 min. RESULTS. Delays in mixed a- and b-waves implicit times were recorded in both wet and dry AMD eyes. Time required to reach 50% of fully recovered responses was delayed in all wet and dry AMD eyes independently of dry AMD severity in the fellow eye. Generalized cone dysfunction and slower activation of the rod phototransduction cascade was noted in a subgroup of patients with advanced features of dry AMD in the fellow eye. CONCLUSIONS. Patients with unilateral wet AMD display rod dysfunction in both their wet and dry AMD eyes. A subset of these patients display, in addition, bilateral cone dysfunction and delayed rod phototransduction activation, which may either reflect extensive morphologic change in advanced stages of AMD and/or represent a distinct phenotypic manifestation within the heterogeneous context of AMD as a disease.
    Investigative ophthalmology & visual science 07/2013; · 3.43 Impact Factor
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    ABSTRACT: The Nile grass rat (Arvicanthis niloticus) has a high proportion of cone photoreceptors (∼30-40%) compared with that in the common laboratory mouse and rat (∼1-3%) and may prove a preferable murine model with which to study cone-driven information processing in retina and primary visual centers. However, other than regions involved in circadian control, little is known about the retinorecipient structures in this rodent. We undertook a detailed analysis of the retinal projections as revealed after intravitreal injection of the anterograde tracer cholera toxin subunit B. Retinal efferents were evaluated in 45 subcortical structures. Contralateral projections were always dominant. Major contralateral inputs consisted of the suprachiasmatic nucleus, dorsolateral geniculate nucleus (dLGN), intergeniculate leaflet, ventral geniculate nucleus (magnocellular part), lateroposterior thalamic nucleus, all six pretectal nuclei, superficial layers of the superior colliculus (SC), and the main nuclei of the accessory optic system. Terminals from the contralateral eye were also localized in an unnamed field rostromedial to the dLGN as well as in the subgeniculate thalamic nucleus. Ipsilateral inputs were found mainly in the suprachiasmatic nucleus, dLGN, intergeniculate leaflet, internal sector of the magnocellular part of the ventral geniculate nucleus, olivary pretectal nucleus, and SC optic layer. Retinal afferents were not detected in the basal forebrain or the dorsal raphe nucleus. Morphometric measurements revealed that the superficial layers of the SC are disproportionately enlarged relative to other retinorecipient regions and brain size compared with rats and mice. We suggest that this reflects the selective projection of cone-driven retinal ganglion cells to the SC. J. Comp. Neurol. 521:1699-1726, 2013. © 2012 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 06/2013; 521(8):Spc1. · 3.66 Impact Factor
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    ABSTRACT: The Nile grass rat (Arvicanthis niloticus) has a high proportion of cone photoreceptors (≈30-40%) compared to that in the common laboratory mouse and rat (≈1-3%), and may prove a preferable murine model to study cone-driven information processing in retina and primary visual centers. However, other than regions involved in circadian control, little is known on retinorecipient structures in this rodent. We undertook a detailed analysis of the retinal projections as revealed after intravitreal injection of the anterograde tracer cholera toxin subunit B. Retinal efferents were evaluated in 45 subcortical structures. Contralateral projections were always dominant. Major contralateral inputs consisted of the suprachiasmatic nucleus, dorsolateral geniculate nucleus (dLGN), intergeniculate leaflet, ventral geniculate nucleus (magnocellular part), lateroposterior thalamic nucleus, all six pretectal nuclei, superficial layers of the superior colliculus (SC) and the main nuclei of the accessory optic system. Terminals from the contralateral eye were also localized in an unnamed field rostromedial to the dLGN as well as in the subgeniculate thalamic nucleus. Ipsilateral inputs were mainly found in the suprachiasmatic nucleus, dLGN, intergeniculate leaflet, internal sector of the magnocellular part of the ventral geniculate nucleus, olivary pretectal nucleus and SC optic layer. Retinal afferents were not detected in the basal forebrain or the dorsal raphe nucleus. Morphometric measurements revealed that the superficial layers of the SC are disproportionately enlarged relative to other retinorecipient regions and brain size when compared to rats and mice. We suggest that this reflects the selective projection of cone-driven retinal ganglion cells to the SC. J. Comp. Neurol., 2013. © 2013 Wiley Periodicals, Inc.
    The Journal of Comparative Neurology 01/2013; · 3.66 Impact Factor
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    ABSTRACT: Retinal dystrophies are predominantly caused by mutations affecting the visual phototransduction system and cilia, with few genes identified that function to maintain photoreceptor survival. We reasoned that growth factors involved with early embryonic retinal development would represent excellent candidates for such diseases. Here we show that mutations in the TGF-β ligand Growth Differentiation Factor 6, which specifies the dorso-ventral retinal axis, contribute to Leber congenital amaurosis. Furthermore, deficiency of gdf6 results in photoreceptor degeneration, so demonstrating a connection between Gdf6 signaling and photoreceptor survival. In addition, in both murine and zebrafish mutant models, we observe retinal apoptosis, a characteristic feature of human retinal dystrophies. Treatment of gdf6-deficient zebrafish embryos with a novel aminopropyl carbazole, P7C3, rescued the retinal apoptosis without evidence of toxicity. These findings implicate for the first time perturbed TGF-β signaling in the genesis of retinal dystrophies, support study of related morphogenetic genes for comparable roles in retinal disease and may offer additional therapeutic opportunities for genetically heterogeneous disorders presently only treatable with gene therapy.
    Human Molecular Genetics 01/2013; · 7.69 Impact Factor
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    ABSTRACT: Multiple Sclerosis is associated with a high incidence of depression, cognitive impairments and neuropathic pain. Previously, we demonstrated that tactile allodynia is present at disease onset in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). We have now monitored changes in object recogntion in mice with EAE to determine if altered nociceptive sensitivity is also associated with behavioural signs indicative of cognitive impairment in this model. At the onset of clinical signs, mice with EAE showed impairments in the novel object recognition (NOR) assay, indicative of deficits in cognitive functioning early in the disease course. At the spinal level, we found increased gene expression for the cytokines IL-1β, IL-6 and the glutamate transporter EAAT-2 that coicinde with increased nociceptive sensitivity and deficits in object recognition. Increased levels of EAAT-2 mRNA appear to be a response to perturbed proteins levels of the transporter as we found a loss of EAAT-2 protein levels in the spinal cord of EAE mice. To determine if changes in the levels of EAAT-2 were responsible for the observed changes in nociceptive sensitivity and cognitive deficits, we treated EAE mice with the β-lactam antibiotic ceftriaxone, an agent know to increase glutamate transporter levels in vivo. Ceftriaxone prevented tactile hypersensitivity and normalized performance in the NOR assay in EAE mice. These findings highlight the important interrelationship between pain and cognitive function in the disease and suggest that targeting spinally mediated pain hypersensitity is a novel therapeutic avenue to treat impairments in other higher order cortical processes.
    Experimental Neurology 01/2013; · 4.65 Impact Factor
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    ABSTRACT: Intra-uterine growth restriction (IUGR) has been associated with increased predisposition to age-related complications. We tested the hypothesis that rat offspring models of IUGR would exhibit exacerbated, age-related retinal dysfunction. Female Sprague-Dawley rats (maintained at 11.5% O2 from gestational day 15 to 21 to induce IUGR) and control offspring (maintained at 21% O2 throughout pregnancy) had retinal function assessed at 2 months (young) and 14 months of age (aged) with electroretinogram (ERG) recordings. Retinal anatomy was assessed by immunofluorescence. Deficits in rod-driven retina function were observed in aged IUGR offspring, as evidenced by reduced amplitudes of dark-adapted mixed a-wave Vmax (by 49.3%, P<0.01), b-wave Vmax (by 42.1%, P<0.001) and dark-adapted peak oscillatory potentials (by 42.3%, P<0.01). In contrast to the rod-driven defects specific to aged IUGR offspring, light adapted ERG recordings revealed cone defects in young animals, that were stationary until old age. At 2 months, IUGR offspring had amplitude reductions for both b-wave (Vmax by 46%, P<0.01) and peak oscillatory potential (Vmax by 38%, P<0.05). Finally, defects in cone-driven responses were further confirmed by reduced maximal photopic flicker amplitudes at 2 (by 42%, P<0.001) and 14 months (by 34%, P = 0.06) and critical flicker fusion frequencies at 14 months (Control: 42±1 Hz, IUGR: 35±2 Hz, P<0.05). These functional changes were not paralleled by anatomical losses in IUGR offspring retinas. These data support that the developing retina is sensitive to stressors, and that pathways governing cone- and rod-driven function differ in their susceptibilities. In the case of prenatal hypoxia, cone- and rod-driven dysfunction manifest at young and old ages, respectively. We must, therefore, take into account the specific impact that fetal programming might exert on age-related retinal dystrophies when considering related diagnoses and therapeutic applications.
    PLoS ONE 01/2013; 8(4):e61861. · 3.53 Impact Factor
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    ABSTRACT: Interneuronal subtype diversity lies at the heart of the distinct molecular properties and synaptic connections that shape the formation of the neuronal circuits that are necessary for the complex spatial and temporal processing of sensory information. Here, we investigate the role of Irx6, a member of the Iroquois homeodomain transcription factor family, in regulating the development of retinal bipolar interneurons. Using a knock-in reporter approach, we show that, in the mouse retina, Irx6 is expressed in type 2 and 3a OFF bipolar interneurons and is required for the expression of cell type-specific markers in these cells, likely through direct transcriptional regulation. In Irx6 mutant mice, presumptive type 3a bipolar cells exhibit an expansion of their axonal projection domain to the entire OFF region of the inner plexiform layer, and adopt molecular features of both type 2 and 3a bipolar cells, highlighted by the ectopic upregulation of neurokinin 3 receptor (Nk3r) and Vsx1. These findings reveal Irx6 as a key regulator of type 3a bipolar cell identity that prevents these cells from adopting characteristic features of type 2 bipolar cells. Analysis of the Irx6;Vsx1 double null retina suggests that the terminal differentiation of type 2 bipolar cells is dependent on the combined expression of the transcription factors Irx6 and Vsx1, but also points to the existence of Irx6;Vsx1-independent mechanisms in regulating OFF bipolar subtype-specific gene expression. This work provides insight into the generation of neuronal subtypes by revealing a mechanism in which opposing, yet interdependent, transcription factors regulate subtype identity.
    Development 12/2012; 139(24):4644-55. · 6.60 Impact Factor
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    ABSTRACT: While some studies on dietary supplementation with docosahexaenoic acid (DHA, 22:6n-3) have reported a beneficial effect on memory as a function of age, others have failed to find any effect. To clarify this issue, we sought to determine whether supplementing mice with a DHA-enriched diet could alter the ability of synapses to undergo activity-dependent changes in the hippocampus, a brain structure involved in forming new spatial memories. We found that DHA was increased by 29% ± 5% (mean ± SE) in the hippocampus for the supplemented (DHA+) versus nonsupplemented (control) group (n = 5 mice per group; p < 0.05). Such DHA elevation was associated with enhanced synaptic transmission (p < 0.05) as assessed by application of a high-frequency electrical stimulation protocol (100 Hz stimulation, which induced transient (<2 h) increases in synaptic strength) to slices from DHA+ (n = 4 mice) hippocampi when compared with controls (n = 4 mice). Increased synaptic responses were evident 60 min poststimulation. These results suggest that dietary DHA supplementation facilitates synaptic plasticity following brief high-frequency stimulation. This increase in synaptic transmission might provide a physiological correlation for the improved spatial learning and memory observed following DHA supplementation.
    Applied Physiology Nutrition and Metabolism 06/2012; 37(5):880-7. · 2.01 Impact Factor
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    ABSTRACT: With age, retina function progressively declines and A2E, a constituent of the toxin lipofuscin, accumulates in retinal pigment epithelial (RPE) cells. Both events are typically exacerbated in age-related retina diseases. We studied the effect of dietary docosahexaenoic acid (DHA, C22:6n-3) supplementation on these events, using a transgenic mouse model (mutant human ELOVL4; E4) displaying extensive age-related retina dysfunction and massive A2E accumulation. Retina function was assessed with the electroretinogram (ERG) and A2E levels were measured in E4 and wildtype (WT) mice. Dietary DHA was manipulated from 1 to 3, 1 to 6, 6 to 12, and 12 to 18 months: 1% DHA over total fatty acids (E4+, WT+) or similar diet without DHA (E4-, WT-). Increased omega-3/6 ratios (DHA/arachidonic acid) in E4+ and WT+ retinas were confirmed for the 1- to 3-month and 1- to 6-month trials. Although 1- to 3-month intervention had no effects, when prolonged to 1 to 6 months, RPE function (ERG c-wave) was preserved in E4+ and WT+. Intervention from 6 to 12 months led to maintained outer and inner retina function (ERG a- and b-wave, respectively) in E4+. At 12 to 18 months, a similar beneficial effect on retina function occurred in WT+; A2E levels were reduced in E4+ and WT+. DHA supplementation was associated with: preserved retina function at mid-degenerative stages in E4 mice; prevention of age-related functional losses in WT mice; and reduced A2E levels in E4 and WT mice at the oldest age examined. These findings imply that dietary DHA could have broad preventative therapeutic applications (acting on pathologic and normal age-related ocular processes).
    Investigative ophthalmology & visual science 03/2012; 53(4):2256-65. · 3.43 Impact Factor
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    ABSTRACT: The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture. In the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam. We conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected level of cellular specificity for the multi-purpose phosphatase, and identify Pten as an integral component of a novel cell positioning pathway in the retina.
    PLoS ONE 01/2012; 7(3):e32795. · 3.53 Impact Factor
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    ABSTRACT: To investigate differentially expressed genes in eyecup and retina of the ELOVL4 transgenic mouse, a model of Stargardt-like macular dystrophy (STGD3). We examined gene and protein expression in known pathways relevant to retinal degeneration using PCR arrays, Western blotting, and immunohistochemistry. Investigations were performed on ELOVL4 transgenic mice at 9 months, when 50% of rod (but no cone) photoreceptors had degenerated. Age-matched wild-type littermates served as controls. Significant expression level changes were found in only 17 of the 252 genes examined. Nine were upregulated (Fgf2, Fgfr1, Ntf5, Cbln1, Ngfr, Ntrk1, Trp53, Tlr6, and Herpud1), and eight were downregulated (Ccl22, Ccr3, Il18rap, Nf1, Ccl11, Atf6β, Rpn1, and Serp1). Overexpression of FGF2 was detected at 1 month, before rod loss onset, and was maintained at high levels until cone loss (18 months). By 9 months, FGF2 overexpression was seen in photoreceptor cell bodies. Increased glial fibrillary acidic protein (GFAP) expression due to glial cell reactivity followed the same time course. Levels of NGFR/p75NTR remained invariant. Although present in rod outer segments at 1 month, the macrophage chemoattracting chemokine CCL22 became undetectable by 9 months, a likely consequence of progressive rod outer segment truncation. At a mid-degeneration stage, major changes in gene expression in the ELOVL4 transgenic mouse retina included upregulation of Fgf2 and Fgfr1 and downregulation of Ccl22. Modulation of FGF2 occurred very early, concomitant with an increase in GFAP expression. Future studies will address which factors upstream of Fgf2 could provide potential therapeutic targets to slow photoreceptor degeneration in STGD3.
    Investigative ophthalmology & visual science 12/2011; 53(2):664-75. · 3.43 Impact Factor
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    ABSTRACT: The discovery of locally produced growth hormone (GH) and its receptor in the retina of rodents raises the possibility that GH might modulate retinal function. To test this hypothesis, we determined the retinal electroretinogram (ERG) of bovine GH (bGH) transgenic mice. ERGs were recorded from 11 wild type (WT) and 9 bGH mice, at 2 months of age in response to a series of light flashes at increasing intensity. Three ERG components were assessed for their amplitude and timing: a-wave, b-wave and oscillatory potentials (OPs). OPs were isolated with a 75-300 Hz digital filter. Retina layer sizes, nuclei number and vascularization were assessed by respectively staining cross sections with DAPI and Bandeiraea simplicifolia. OPs were selectively affected in the bGH mouse compared to WT. When OP amplitude values were normalized to the a-wave amplitude (to account for inter-animal variability in WT and bGH groups), OP2, OP3, and OP4 showed amplitude reductions (of 65%, 72%, and 68%, respectively) in the bGH mouse compared to the WT. This was accompanied by a prolongation of the implicit time for the peak of OP3 (28.1 vs 31.1 ms, WT vs bGH) and OP4 (37.8 vs 41.6 ms), while the implicit time of a- and b-waves were unaffected. Fast Fourier transform analysis revealed that the OPs' dominant frequency was significantly reduced (P<0.05) in the bGH mice (100 Hz) compared to WT (108Hz). There was no significant change in retinal histology except for a significant increase in the axial length of the eye in bGH mice. Mice expressing bGH display a selective inner retinal defect as demonstrated using ERG recordings. The specific OP defect observed in these mice is similar to the ERG results obtained in patients with diabetic retinopathy and in related animal models.
    Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 06/2011; 21(4):219-27. · 2.35 Impact Factor
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    ABSTRACT: We evaluated the full field electroretinogram (ERG) to assess age-related changes in retina function in humans. ERG recordings were performed on healthy subjects with normal fundus appearance, lack of cataract and 20/20 acuity, aged 20-39 years (n = 27; mean age 25 ± 5, standard deviation), 40-59 years (n = 20; mean 53 ± 5), and 60-82 years (n = 18; mean 69 ± 5). Multiple ERG tests were applied, including light and dark-adapted stimulus-response function, dark adaptation and dynamic of recovery from a single bright flash under dark-adapted conditions. Changes in ERG properties were found in the oldest age group when compared with the two younger age groups. (1) The photopic hill effect was less pronounced. (2) Both photopic a-wave and b-wave amplitudes and implicit times were increased at high stimulus strengths. (3) Dark adaptation time was delayed for pure rod and L/M cone-driven responses, respectively. (4) Dark-adapted a-wave but not b-wave amplitudes were reduced, yielding higher B/A ratios. (5) Dark-adapted a- and b-waves implicit times were prolonged: there was a direct proportional correlation between minimal a-wave implicit times and age. (6) The dynamic of dark current recovery from a bright flash, under dark-adapted conditions, was transiently faster at intervals between 0.9 and 2 s. These results denote that aging of the healthy retina is accompanied by specific functional changes, which must be taken into account to optimally diagnose potential pathologies.
    Documenta Ophthalmologica 06/2011; 122(3):177-90. · 1.54 Impact Factor
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    ABSTRACT: Lung hypoplasia and persistent pulmonary hypertension of the newborn limit survival in congenital diaphragmatic hernia (CDH). Unlike other diseases resulting in persistent pulmonary hypertension of the newborn, infants with CDH are refractory to inhaled nitric oxide (NO). Nitric oxide mediates pulmonary vasodilatation at birth in part via cyclic GMP production. Phosphodiesterase type 5 (PDE5) limits the effects of NO by inactivation of cyclic GMP. Because of the limited success in postnatal management of CDH, we hypothesized that antenatal PDE5 inhibition would attenuate pulmonary artery remodeling in experimental nitrofen-induced CDH. Nitrofen administered at embryonic day 9.5 to pregnant rats resulted in a 60% incidence of CDH in the offspring and recapitulated features seen in human CDH, including structural abnormalities (lung hypoplasia, decreased pulmonary vascular density, pulmonary artery remodeling, right ventricular hypertrophy), and functional abnormalities (decreased pulmonary artery relaxation in response to the NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide). Antenatal sildenafil administered to the pregnant rat from embryonic day 11.5 to embryonic day 20.5 crossed the placenta, increased fetal lung cyclic GMP and decreased active PDE5 expression. Antenatal sildenafil improved lung structure, increased pulmonary vessel density, reduced right ventricular hypertrophy, and improved postnatal NO donor 2-(N,N-diethylamino)-diazenolate-2-oxide-induced pulmonary artery relaxation. This was associated with increased lung endothelial NO synthase and vascular endothelial growth factor protein expression. Antenatal sildenafil had no adverse effect on retinal structure/function and brain development. Antenatal sildenafil improves pathological features of persistent pulmonary hypertension of the newborn in experimental CDH and does not alter the development of other PDE5-expressing organs. Given the high mortality/morbidity of CDH, the potential benefit of prenatal PDE5 inhibition in improving the outcome for infants with CDH warrants further studies.
    Circulation 05/2011; 123(19):2120-31. · 15.20 Impact Factor
  • Circulation. 05/2011; 123(19):2120-31.

Publication Stats

2k Citations
261.89 Total Impact Points

Institutions

  • 2006–2014
    • University of Alberta
      • • Department of Ophthalmology
      • • Department of Biochemistry
      Edmonton, Alberta, Canada
  • 2009
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
    • Aragon Health Sciences Institute
      Caesaraugusta, Aragon, Spain
  • 2007
    • University of Wisconsin–Madison
      Madison, Wisconsin, United States
  • 2002–2007
    • University of Utah
      • • John Moran Eye Center
      • • Department of Ophthalmology and Visual Sciences
      Salt Lake City, UT, United States
  • 2004
    • Hospital Universitario Miguel Servet
      Caesaraugusta, Aragon, Spain
  • 1999–2002
    • University of Murcia
      • Faculty of Medicine
      Murcia, Murcia, Spain
    • Russian Academy of Sciences
      • Institute of Developmental Biology
      Moscow, Moscow, Russia
  • 2000
    • University College London
      • Institute of Ophthalmology
      London, ENG, United Kingdom
  • 1995
    • McGill University
      • Centre for Research in Neuroscience
      Montréal, Quebec, Canada