Medical College of Wisconsin
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Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells. J Neurosci 2013 Sep 18;33(38):14989-97

Date

09/21/2013

Pubmed ID

24048828

Pubmed Central ID

PMC3776053

DOI

10.1523/JNEUROSCI.2039-13.2013

Scopus ID

2-s2.0-84884173918 (requires institutional sign-in at Scopus site)   66 Citations

Abstract

Spatial variation in light intensity, called spatial contrast, comprises much of the visual information perceived by mammals, and the relative ability to detect contrast is referred to as contrast sensitivity (Purves et al., 2012). Recently, retinal dopamine D4 receptors (D4Rs) have been implicated in modulating contrast sensitivity (Jackson et al., 2012); however, the cellular and molecular mechanisms have not been elucidated. Our study demonstrates a circadian rhythm of contrast sensitivity that peaks during the daytime, and that its regulation involves interactions of D4Rs, the clock gene Npas2, and the clock-controlled gene adenylyl cyclase 1 (Adcy1) in a subset of retinal ganglion cells (RGCs). Targeted disruption of the gene encoding D4Rs reduces the amplitude of the contrast sensitivity rhythm by reducing daytime sensitivity and abolishes the rhythmic expression of Npas2 and Adcy1 mRNA in the ganglion cell layer (GCL) of the retina. Npas2(-/-) and Adcy1(-/-) mice show strikingly similar reductions in the contrast sensitivity rhythm to that in mice lacking D4Rs. Moreover, Adcy1 transcript rhythms were abolished in the GCL of Npas2(-/-) mice. Luciferase reporter assays demonstrated that the Adcy1 promoter is selectively activated by neuronal PAS-domain protein 2 (NPAS2)/BMAL1. Our results indicate that the contrast sensitivity rhythm is modulated by D4Rs via a signaling pathway that involves NPAS2-mediated circadian regulation of Adcy1. Hence, we have identified a circadian clock mechanism in a subset of RGCs that modulates an important aspect of retinal physiology and visual processing.

Author List

Hwang CK, Chaurasia SS, Jackson CR, Chan GC, Storm DR, Iuvone PM

Author

Shyam S. Chaurasia PhD Professor in the Ophthalmology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

ARNTL Transcription Factors
Adenylyl Cyclases
Animals
Cell Line, Transformed
Circadian Rhythm
Contrast Sensitivity
Dopamine
Gene Expression Regulation
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Nerve Tissue Proteins
Photic Stimulation
Receptors, Dopamine D4
Retina
Retinal Ganglion Cells
Signal Transduction
Transfection
Visual Acuity
Visual Pathways
beta-Galactosidase