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Erica Landis, Victoria Yang, Li He, Kelly Lohr, P. Michael Iuvone, Machelle T Pardue; Altered dopamine release in VMAT2 mutant mice has little effect on refractive development. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5637.
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© ARVO (1962-2015); The Authors (2016-present)
The purpose of this work is to determine the role of dopamine (DA) as a potential stop signal for refractive development and myopia susceptibility in mice. Vesicular monoamine transporter 2 (VMAT2) is responsible for packaging DA into vesicles for release. Thus, we hypothesize that increasing or decreasing expression of VMAT2 will enhance or diminish DA release, thereby altering refractive error during development.
Three groups of mice were used for these experiments; C57BL/6 mice over-expressing VMAT2 (VMAT2 HI), wild-type littermates (WT), and VMAT2 under-expressing mice (VMAT2 LO). To confirm changes in DA signaling, we measured VMAT2 expression in the retina with western blots and the retinal levels of DA and DOPAC with HPLC. The refractive development of each genotype was studied with biweekly measurements of refractive error, keratometry, and axial length from post-natal day 28 (P28) until P112 (HI n=16, WT n=8, LO n=7). To determine functional differences caused by changes in VMAT2 expression, optokinetic tracking was used to measure spatial frequency and contrast sensitivity thresholds of adult mice (HI n=3, WT n=4, LO n=3).
Western blotting confirmed increased retinal VMAT2 expression in the HI mice relative to the WTs and LOs. HPLC analysis showed that retinal dopamine levels in the LO mice were reduced by 68.3% compared to WT mice (p<0.001). In addition, retinal DOPAC was reduced in VMAT2 LO mice by 40.8% relative to WTs (p<0.01). HI and WT mice had similar levels of dopamine and DOPAC. Refractive errors of VMAT2 LO mice were significantly more hyperopic than HI and WT mice at P28 only (HI 2.78±0.43D; WT 1.93±0.77; LO 4.49±0.91). No significant differences were found in keratometry or axial length between the genotypes. Spatial frequency and contrast sensitivity thresholds were similar across HI, WT and LO mice (SF HI: 0.40±0.003, WT: 0.40±0.006, LO: 0.40±0.004, CS HI: 9.78±0.13, WT: 9.76±0.42, LO: 9.62±0.44).
These results indicate that altered DA release modulates only early refractive development under normal laboratory conditions. The absence of changes in visual function suggest that modulations of VMAT2 may not alter DA release to critical levels or that potential compensatory mechanisms exist, which may also explain the lack of effect on refractive development. Future studies will test susceptibility of VMAT2 mutants to form deprivation myopia.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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