Visually-Driven Ocular Growth in Mice Requires Functional Rod Photoreceptors

Park, Han Na; Jabbar, Seema B.; Tan, Christopher C.; Sidhu, Curran; Abey, Jane; Aseem, Fazila; Schmid, Gregor; Iuvone, P. Michael; Pardue, Machelle T.

doi:10.1167/iovs.14-14648

Cited by 58 publications

(67 citation statements)

References 73 publications

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“…54 Obviously, differences in routes of drug administration (intravitreal injection in chickens and intraperitoneal injection in our study) lead to different drug distributions within the retina. During FDM development, the unchanged dopamine level in mice 12,13,36 is also different from the reduced dopamine level in chickens. 6,11 However, with respect to the active status of dopamine receptors, which is the most important point while considering the receptor mechanism of APO activity, genetic KO provides an alternative approach that is much more complete and persistent than pharmacologic intervention.…”

Section: D1r-dependent Mechanism Of Apomorphine In Myopiamentioning

confidence: 86%

“…8,21 Although the stability of retinal dopamine during FDM development in mice is different from the decreased levels in other species, [12][13][14] daily systemic APO injection in mice nevertheless offers protection against FDM development by at least 75%, in agreement with other species. 22 Therefore, the mouse is not an outlier compared with other animal models with respect to the development of FDM and responses to APO.…”

mentioning

confidence: 91%

“…11 Unlike FDM in chickens, recent studies showed that retinal dopamine levels remained unaltered in FDM C57BL/6 mice. [12][13][14] These results suggest that subtle, but as yet undetected, changes of the retinal dopamine levels and/ or changes in other aspects of the dopaminergic system could be altered by FDM in mice. Administration of 6-hydroxydopamine (6-OHDA) significantly reduced the retinal dopamine level in mice and resulted in relative myopic refractive errors under normal visual environments and an enhanced FDM response.…”

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confidence: 99%

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Dopamine D1 Receptors Contribute Critically to the Apomorphine-Induced Inhibition of Form-Deprivation Myopia in Mice

Huang

Zhang

Wang

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine the roles of dopamine D2 receptors (D2Rs) and dopamine D1 receptors (D1Rs) in the inhibition of form-deprivation myopia (FDM) by the nonselective dopamine agonist apomorphine (APO) in D2R-knockout (D2R-KO) and D1R-KO mice. METHODS.Retinal layer thicknesses and electroretinograms (ERGs) were analyzed in KO mice and in D2R and D1R antagonist-treated mice. D2R-KO or D1R-KO mice and wild-type (WT) littermates were subjected to form deprivation during postnatal weeks 5 to 8. Both groups were intraperitoneally injected daily with either APO (5 lg/g body weight) dissolved in 1 lg/ lL ascorbic acid or vehicle alone. Refraction, vitreous chamber depth (VCD), and axial length (AL), among other parameters, were measured prior to and at the end of the treatment period.RESULTS. The retinal layer thicknesses and ERGs in KO mice were similar to those treated with D2R and D1R antagonists. APO administration in WT mice inhibited the development of FDM by approximately 80%. FDM in D2R-KO mice was inhibited approximately 50% compared with WT mice and was further inhibited by APO to a level similar to that in APO-treated WT mice. FDM development in D1R-KO mice was similar to that in WT mice and was not affected by APO administration. The changes in VCD and AL were consistent with refraction data.CONCLUSIONS. In mice, APO-mediated FDM inhibition was abolished by D1R KO but not D2R KO. This indicates the specificity of D1Rs for the pharmacologic inhibitory effect of APO on FDM and a nonessential role of D2Rs in this process in mice.

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Section: D1r-dependent Mechanism Of Apomorphine In Myopiamentioning

confidence: 86%

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confidence: 91%

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confidence: 99%

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Dopamine D1 Receptors Contribute Critically to the Apomorphine-Induced Inhibition of Form-Deprivation Myopia in Mice

Huang

Zhang

Wang

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…For the FD experiments, retinas of mGluR6−/− (control: n=5, goggled: n=5) were harvested after the final end point at 6 weeks of age. Given the evidence that C57BL/6 WT mice (Wu et al, 2015) or WT mice of different backgrounds (Chakraborty et al, 2014; Park et al, 2013; Park et al, 2014) do not show significant changes in retinal DA levels with imposed FD, changes in retinal dopamine activity for goggled WT animals were not measured in this study. To avoid the effects of anesthesia on measurements, all experimental mouse retinas were collected 48 hours after the final measurements.…”

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confidence: 97%

“…Furthermore, alternations in ON and OFF responses using 2-amino-4 phosphonobutyric acid (APB) or cis 2,3 piperidine-dicarboxylic acid (PDA) in chickens influence the ocular growth patterns and refractive errors (Crewther et al, 1996). More recent studies using various mutant mouse models have provided stronger evidence of retinal involvement in ocular refractive development (Chakraborty et al, 2014; Pardue et al, 2008; Park et al, 2013; Park et al, 2014). Mouse models ensure complete and selective blockage of a single pathway, and allow examination of the interaction between genetic background and visual environment in refractive development (Pardue et al, 2013).…”

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confidence: 99%

ON pathway mutations increase susceptibility to form-deprivation myopia

Chakraborty

Park

Hanif

et al. 2015

Experimental Eye Research

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The ON pathway mutation in nob mice is associated with altered refractive development, and an increased susceptibility to form-deprivation (FD) myopia. In this study, we used mGluR6−/− mice, another ON pathway mutant, to determine whether the nob phenotype was due to the Nyx mutation or abnormal ON pathway transmission. Refractive development under a normal visual environment for mGluR6−/− and age-matched wild-type (WT) mice was measured every 2 weeks from 4 to 16 weeks of age. The response to monocular FD from 4 weeks of age was measured weekly in a separate cohort of mice. Refraction and ocular biometry were obtained using a photorefractor and optical coherence tomography. Retinas were harvested at 16 weeks, and analyzed for dopamine (DA) and DOPAC using high-performance liquid chromatography. Under normal conditions, mGluR6−/− mice were significantly more myopic than their WT controls (refraction at 12 weeks; WT: 9.40 ± 0.16 D, mGluR6−/−: 6.91 ± 0.38 D). Similar to nob mice, two weeks of FD resulted in a significant myopic shift of −5.57 ± 0.72 D in mGluR6−/− mice compared to −1.66 ± 0.19 D in WT animals. No significant axial length changes were observed with either normal or FD visual conditions. At 16 weeks, mGluR6−/− retinas showed significantly lower DOPAC levels (111.2 ± 33.0 pg/mg) compared to their WT counterparts (197.5 ± 11.2 pg/mg). Retinal DA levels were similar between the different genotypes. Our results indicate that reduced retinal DA metabolism/turnover may be associated with increased susceptibility to myopia in mice with ON pathway defect mutations.

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Single‐cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell‐type‐specific mechanisms

Yao,

Chen,

et al. 2023

MedComm

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High myopia is a leading cause of blindness worldwide with increasing prevalence. Retina percepts visual information and triggers myopia development, but the underlying etiology is not fully understood because of cellular heterogeneity. In this study, single‐cell RNA sequencing analysis was performed on retinas of mouse highly myopic and control eyes to dissect the involvement of each cell type during high myopia progression. For highly myopic photoreceptors, Hk2 inhibition underlying metabolic remodeling from aerobic glycolysis toward oxidative phosphorylation and excessive oxidative stress was identified. Importantly, a novel Apoe+ rod subpopulation was specifically identified in highly myopic retina. In retinal neurons of highly myopic eyes, neurodegeneration was generally discovered, and the imbalanced ON/OFF signaling driven by cone‐bipolar cells and the downregulated dopamine receptors in amacrine cells were among the most predominant findings, indicating the aberrant light processing in highly myopic eyes. Besides, microglia exhibited elevated expression of cytokines and TGF‐β receptors, suggesting enhanced responses to inflammation and the growth‐promoting states involved in high myopia progression. Furthermore, cell–cell communication network revealed attenuated neuronal interactions and increased glial/vascular interactions in highly myopic retinas. In conclusion, this study outlines the transcriptional landscape of highly myopic retina, providing novel insights into high myopia development and prevention.

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Visually-Driven Ocular Growth in Mice Requires Functional Rod Photoreceptors

Abstract: Functional rod photoreceptors are critical to normal refractive development and the response to FD in mice. Dopamine levels may not directly modulate the refractive state of the mouse eye, but tonic levels of dopamine during development may determine susceptibility to myopia.

Cited by 58 publications

References 73 publications

Dopamine D1 Receptors Contribute Critically to the Apomorphine-Induced Inhibition of Form-Deprivation Myopia in Mice

Dopamine D1 Receptors Contribute Critically to the Apomorphine-Induced Inhibition of Form-Deprivation Myopia in Mice

ON pathway mutations increase susceptibility to form-deprivation myopia

Single‐cell RNA sequencing of retina revealed novel transcriptional landscape in high myopia and underlying cell‐type‐specific mechanisms

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