Browsing by Subject "Electroretinography"

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    ItemOpen Access
    Activation of Rod Input in a Model of Retinal Degeneration Reverses Retinal Remodeling and Induces Formation of Functional Synapses and Recovery of Visual Signaling in the Adult Retina.
    (The Journal of neuroscience : the official journal of the Society for Neuroscience, 2019-08) Wang, Tian; Pahlberg, Johan; Cafaro, Jon; Frederiksen, Rikard; Cooper, AJ; Sampath, Alapakkam P; Field, Greg D; Chen, Jeannie
    A major cause of human blindness is the death of rod photoreceptors. As rods degenerate, synaptic structures between rod and rod bipolar cells disappear and the rod bipolar cells extend their dendrites and occasionally make aberrant contacts. Such changes are broadly observed in blinding disorders caused by photoreceptor cell death and are thought to occur in response to deafferentation. How the remodeled retinal circuit affects visual processing following rod rescue is not known. To address this question, we generated male and female transgenic mice wherein a disrupted cGMP-gated channel (CNG) gene can be repaired at the endogenous locus and at different stages of degeneration by tamoxifen-inducible cre-mediated recombination. In normal rods, light-induced closure of CNG channels leads to hyperpolarization of the cell, reducing neurotransmitter release at the synapse. Similarly, rods lacking CNG channels exhibit a resting membrane potential that was ~10 mV hyperpolarized compared to WT rods, indicating diminished glutamate release. Retinas from these mice undergo stereotypic retinal remodeling as a consequence of rod malfunction and degeneration. Upon tamoxifen-induced expression of CNG channels, rods recovered their structure and exhibited normal light responses. Moreover, we show that the adult mouse retina displays a surprising degree of plasticity upon activation of rod input. Wayward bipolar cell dendrites establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings demonstrate remarkable plasticity extending beyond the developmental period and support efforts to repair or replace defective rods in patients blinded by rod degeneration.SIGNIFICANCE STATEMENT Current strategies for treatment of neurodegenerative disorders are focused on the repair of the primary affected cell type. However, the defective neurons function within a complex neural circuitry, which also becomes degraded during disease. It is not known whether rescued neurons and the remodeled circuit will establish communication to regain normal function. We show that the adult mammalian neural retina exhibits a surprising degree of plasticity following rescue of rod photoreceptors. The wayward dendrites of rod bipolar cells re-establish contact with rods to support normal synaptic transmission, which is propagated to the retinal ganglion cells. These findings support efforts to repair or replace defective rods in patients blinded by rod cell loss.
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    ItemOpen Access
    Baseline Visual Field Findings in the RUSH2A Study: Associated Factors and Correlation With Other Measures of Disease Severity.
    (American journal of ophthalmology, 2020-11) Duncan, Jacque L; Liang, Wendi; Maguire, Maureen G; Audo, Isabelle; Ayala, Allison R; Birch, David G; Carroll, Joseph; Cheetham, Janet K; Esposti, Simona Degli; Durham, Todd A; Erker, Laura; Farsiu, Sina; Ferris, Frederick L; Heon, Elise; Hufnagel, Robert B; Iannaccone, Alessandro; Jaffe, Glenn J; Kay, Christine N; Michaelides, Michel; Pennesi, Mark E; Sahel, José-Alain; Foundation Fighting Blindness Consortium Investigator Group

    Purpose

    To report baseline visual fields in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study.

    Design

    Cross-sectional study within a natural history study.

    Methods

    Setting: multicenter, international.

    Study population

    Usher syndrome type 2 (USH2) (n = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) (n = 47) associated with biallelic disease-causing sequence variants in USH2A.

    Observation procedures

    Repeatability of full-field static perimetry (SP) and between-eye symmetry of kinetic perimetry (KP) were evaluated with intraclass correlation coefficients (ICCs). The association of demographic and clinical characteristics with total hill of vision (VTOT) was assessed with general linear models. Associations between VTOT and other functional and morphologic measures were assessed using Spearman correlation coefficients and t tests.

    Main outcome measures

    VTOT (SP) and III4e isopter area (KP).

    Results

    USH2 participants had more severe visual field loss than ARRP participants (P < .001, adjusting for disease duration, age of enrollment). Mean VTOT measures among 3 repeat tests were 32.7 ± 24.1, 31.2 ± 23.4, and 31.7 ± 23.9 decibel-steradians (intraclass correlation coefficient [ICC] = 0.96). Better VA, greater photopic ERG 30-Hz flicker amplitudes, higher mean microperimetry sensitivity, higher central subfield thickness, absence of macular cysts, and higher III4e seeing area were associated with higher VTOT (all r > .48; P < .05). Mean III4e isopter areas for left (4561 ± 4426 squared degrees) and right eyes (4215 ± 4300 squared degrees) were concordant (ICC = 0.94).

    Conclusions

    USH2 participants had more visual field loss than participants with USH2A-related ARRP, adjusting for duration of disease and age of enrollment. VTOT was repeatable and correlated with other functional and structural metrics, suggesting it may be a good summary measure of disease severity in patients with USH2A-related retinal degeneration.
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    ItemOpen Access
    RanBP2 modulates Cox11 and hexokinase I activities and haploinsufficiency of RanBP2 causes deficits in glucose metabolism.
    (PLoS Genet, 2006-10) Aslanukov, Azamat; Bhowmick, Reshma; Guruju, Mallikarjuna; Oswald, John; Raz, Dorit; Bush, Ronald A; Sieving, Paul A; Lu, Xinrong; Bock, Cheryl B; Ferreira, Paulo A
    The Ran-binding protein 2 (RanBP2) is a large multimodular and pleiotropic protein. Several molecular partners with distinct functions interacting specifically with selective modules of RanBP2 have been identified. Yet, the significance of these interactions with RanBP2 and the genetic and physiological role(s) of RanBP2 in a whole-animal model remain elusive. Here, we report the identification of two novel partners of RanBP2 and a novel physiological role of RanBP2 in a mouse model. RanBP2 associates in vitro and in vivo and colocalizes with the mitochondrial metallochaperone, Cox11, and the pacemaker of glycolysis, hexokinase type I (HKI) via its leucine-rich domain. The leucine-rich domain of RanBP2 also exhibits strong chaperone activity toward intermediate and mature folding species of Cox11 supporting a chaperone role of RanBP2 in the cytosol during Cox11 biogenesis. Cox11 partially colocalizes with HKI, thus supporting additional and distinct roles in cell function. Cox11 is a strong inhibitor of HKI, and RanBP2 suppresses the inhibitory activity of Cox11 over HKI. To probe the physiological role of RanBP2 and its role in HKI function, a mouse model harboring a genetically disrupted RanBP2 locus was generated. RanBP2(-/-) are embryonically lethal, and haploinsufficiency of RanBP2 in an inbred strain causes a pronounced decrease of HKI and ATP levels selectively in the central nervous system. Inbred RanBP2(+/-) mice also exhibit deficits in growth rates and glucose catabolism without impairment of glucose uptake and gluconeogenesis. These phenotypes are accompanied by a decrease in the electrophysiological responses of photosensory and postreceptoral neurons. Hence, RanBP2 and its partners emerge as critical modulators of neuronal HKI, glucose catabolism, energy homeostasis, and targets for metabolic, aging disorders and allied neuropathies.
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    ItemOpen Access
    The RUSH2A Study: Best-Corrected Visual Acuity, Full-Field Electroretinography Amplitudes, and Full-Field Stimulus Thresholds at Baseline.
    (Translational vision science & technology, 2020-10-08) Birch, David G; Cheng, Peiyao; Duncan, Jacque L; Ayala, Allison R; Maguire, Maureen G; Audo, Isabelle; Cheetham, Janet K; Durham, Todd A; Fahim, Abigail T; Ferris, Frederick L; Heon, Elise; Huckfeldt, Rachel M; Iannaccone, Alessandro; Khan, Naheed W; Lad, Eleonora M; Michaelides, Michel; Pennesi, Mark E; Stingl, Katarina; Vincent, Ajoy; Weng, Christina Y; Foundation Fighting Blindness Consortium Investigator Group

    Purpose

    The purpose of this study was to evaluate baseline best corrected visual acuity (BCVA), full-field electroretinography (ERG), full-field stimulus thresholds (FST), and their relationship with baseline demographic and clinical characteristics in the Rate of Progression in Usher syndrome type 2 (USH2A)-related Retinal Degeneration (RUSH2A) multicenter study.

    Methods

    Participants had Usher syndrome type 2 (USH2, N = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP, N = 47) associated with biallelic variants in the USH2A gene. Associations of demographic and clinical characteristics with BCVA, ERG, and FST were assessed with regression models.

    Results

    In comparison to ARRP, USH2 had worse BCVA (median 79 vs. 82 letters; P < 0.001 adjusted for age), lower rod-mediated ERG b-wave amplitudes (median 0.0 vs. 6.6 µV; P < 0.001) and 30 Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 µV; P = 0.001), and higher (white, blue, and red) FST thresholds (means [-26, -31, -23 dB] vs. [-39, -45, -28 dB]; P < 0.001 for all stimuli). After adjusting for age, gender, and duration of vision loss, the difference in BCVA between diagnosis groups was attenuated (P = 0.09). Only diagnosis was associated with rod- and cone-mediated ERG parameters, whereas both genders (P = 0.04) and duration of visual loss (P < 0.001) also were associated with FST white stimulus.

    Conclusions

    USH2 participants had worse BCVA, ERG, and FST than ARRP participants. FST was strongly associated with duration of disease; it remains to be determined whether it will be a sensitive measure of progression.

    Translational relevance

    Using standardized research protocols in RUSH2A, measures have been identified to monitor disease progression and treatment response and differentiate features of prognostic relevance between USH2 and ARRP participants with USH2A mutations.