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P. M. Iuvone, J. Abey, N. Pozdeyev, C. R. Jackson; Targeted Disruption of the Dopamine D4 Receptor Gene (Drd4) Alters Retinal Gene Expression and Visual Function. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1067.
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© ARVO (1962-2015); The Authors (2016-present)
Dopamine D4 receptors (D4Rs) are abundant in retina where they are expressed by photoreceptors and inner retinal neurons. D4Rs regulate cAMP formation and protein phosphorylation in photoreceptor cells. This study was conducted to assess changes in gene expression and visual function in mice lacking D4Rs due to targeted disruption of the Drd4 gene.
C57Bl/6 (wild type, WT), and Drd4-/- and Adcy1-/- mice on a C57Bl/6 background were housed on a 12h:12h light-dark cycle. Affymetrix microarray analysis was performed on retinas of Drd4-/- and WT littermates dissected approximately 4 hrs after light onset. Results were confirmed by qRT-PCR. Visual function was investigated in WT, Drd4-/- and Adcy1-/- mice using optokinetic tracking to assess acuity and contrast sensitivity.
Expression profiling using conservative filtering (5% false discovery rate) found 50 genes that are differentially expressed in Drd4-/- retinas compared to WT controls. Proteins encoded by the transcripts are involved in signal transduction (e.g., Adcy1, Rgs20, Guca1b), gene expression (e.g., Hdac9), alternative mRNA splicing (e.g., Mbln2), water transport (Aqp1), and a variety of other cellular functions. Some of these genes were expressed as daily rhythms in WT mice, but these rhythms were disrupted in Drd4-/- mice. Visual acuity in Drd4-/- mice was similar to that in WT mice. However, contrast sensitivity at all spatial frequencies except the highest detectable frequencies was dramatically reduced in Drd4-/- compared to controls. DRD4s in photoreceptor cells signal, at least in part, through the type 1 adenylyl cyclase, which is encoded by Adcy1. Accordingly, contrast sensitivity was also reduced in Adcy1-/- mice compared to WT controls, although not to the same degree as in Drd4-/- mice.
Lack of DRD4 results in significant changes in retinal gene expression and visual contrast sensitivity in the mammalian retina. Changes in visual function in Drd4-/- mice may be mediated by decreased expression of the type 1 adenylyl cyclase, but other mechanisms may also be involved.
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