Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light‐evoked translocation in vivo

Abstract

Rod tetrameric arrestin 1 (tet-ARR1), stored in the outer nuclear layer/inner segments in the dark, modulates photoreceptor synaptic activity; light exposure stimulates a reduction via translocation to the outer segments for terminating G-protein coupled phototransduction signaling. Here, we test the hypothesis that intraretinal spin-lattice relaxation rate in the rotating frame (1/T1r), an endogenous MRI contrast mechanism, has high potential for evaluating rod tet-ARR1 and its reduction via translocation. Dark-and light-exposed mice (null for the ARR1 gene, overexpressing ARR1, diabetic, or wild type with or without treatment with Mn 2+ , a calcium channel probe) were studied using 1/T1r MRI. Immunohistochemistry and single-cell recordings of the retinas were also performed. In wild-type mice with or without treatment with Mn 2+ , 1/T1r of avascular outer retina (64% to 72% depth) was significantly (P < 0.05) greater in the dark than in the light; a significant (P < 0.05) but opposite pattern was noted in the inner retina (<50% depth). Light-evoked outer retina D1/T1r was absent in ARR1-null mice and supernormal in overexpressing mice. In diabetic mice, the outer retinal D1/T1r pattern suggested normal darkto-light tet-ARR1 translocation and chromophore content, conclusions confirmed ex vivo. Light-stimulated D1/ T1r in inner retina was linked to changes in blood volume. Our data support 1/T1r MRI for noninvasively assessing rod tet-ARR1 and its reduction via protein translocation, which can be combined with other metrics of retinal function in vivo.-Berkowitz, B. A., Gorgis, J., Patel, A., Baameur, F., Gurevich, V. V., Craft, C. M., Kefalov, V. J., Roberts, R. Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light-evoked translocation in vivo. FASEB J. 29, 554-564 (2015). www.fasebj.org

Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

“…Thus, at the present resolution, we previously demonstrated that MRI can distinguish rod inner segment from outer segment based on the light-evoked expansion of the subretinal space in mice and rats, as well as, for example, (1) inner from outer retina manganese uptake as a function of light, (2) DIL-induced suppression of only inner retinal manganese uptake, and (3) the outer nuclear layer-only tetrameric visual arrestin 1 and its reduction via light-evoked translocation. 28,29,50,51 These examples strongly support our claim that the resolution of MRI is sufficient for extracting meaningful layer-specific functional data in vivo. In all cases, animals were humanely euthanized as detailed in our IACUCapproved protocol.…”

“…14,[23][24][25][26][27] However, subsequent studies have not found any evidence for a visual cycle defect in diabetic mice. 28 Thus, the mechanism by which 11-cis-retinaldehyde exerts its beneficial action in the diabetic mouse retina is still unclear.…”

Retinylamine Benefits Early Diabetic Retinopathy in Mice

“…Retinyl esters participate in 11-cis-retinal formation (49) and are shown herein to accumulate to supranormal levels in diabetic retina, suggesting an impairment of retinoid dynamics in diabetic mice. However, other investigators (58) have not found evidence of abnormal visual cycle activity in diabetes. Maintenance of the visual cycle requires support from numerous mitochondria in photoreceptor cells, and our previous evidence (17,37) suggests that much of the superoxide generated by the retina in diabetes is generated by such mitochondria.…”

MRI of rod cell compartment-specific function in disease and treatment in vivo

“…Thus, MRI evaluates the same set of rod cells for compartment-specific function in vivo using different types of acquisitions (see below for details; summarized in Fig. 4) (Berkowitz et al, , 2015a(Berkowitz et al, , 2015cBissig and Berkowitz, 2012). In addition, four "free" metrics are also obtained: retinal and choroidal thickness, and light-dependent expansion of the inner retinal circulation and choroid (Fig.…”

“…Thus, two additional MRI indices of rod cell functione measured without administration of exogenous contrast agents e have been developed to complement MEMRI and to facilitate translation of MRI of retinal function into humans. These methods are i) apparent diffusion coefficient (ADC) MRI, which measures light-evoked expansion of both SRS [controlled in part by the photoreceptors and in part by the retinal pigment epithelium (RPE)] and of the choroid (Berkowitz et al, 2015a;Bissig and Berkowitz, 2012), and ii) measurement of the spin-lattice relaxation rate in the rotating-frame (1/T1r) which evaluates lightstimulated rod arrestin and its translocation, together with retinal vessel expansion (Berkowitz et al, 2015c). As summarized in Fig.…”