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Samer Hattar, David S. McNeill, Jennifer L. Ecker, Kylie Chew; Iprgcs Are Critical For The Proper Development Of The Circadian Clock. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2723.
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© ARVO (1962-2015); The Authors (2016-present)
In mammals, all light information is detected by the retina and relayed to the brain through the retinal ganglion cells (RGCs). A subset of RGCs express the photopigment melanopsin (Opn4) and are intrinsically photosensitive (ipRGCs). ipRGCs are the sole conduit by which light information is relayed to regions of the brain that are responsible for non-image forming functions such as photoentrainment, sleep, and pupillary light reflex (PLR). It is known that retinal input during development is required for establishing proper circuitry and function of retinal targets in the brain. While the role of the retina and light detection in the development of the circadian clock has previously been considered minor, we aimed to determine if ipRGCs input to non-image forming centers of the brain is important for the proper development of circadian rhythms.
We previously generated mice that express attenuated diphtheria toxin (aDTA) from the endogenous melanopsin locus to genetically ablate ipRGCs. In these mice, the majority of ipRGCs are retained during development and are progressively lost throughout adulthood. Homozygous Opn4aDTA/aDTA mice can perform visually guided behaviors yet the majority of these mice are unable to photoentrain and free-run in constant darkness with a period similar to wild type mice. To address the developmental role for ipRGCs, we expressed a non-attenuated form of the diphtheria toxin (DTA) under the melanopsin promoter to genetically ablate ipRGCs during development (Opn4DTA/DTA mice).
In these mice, the total number of ipRGCs killed is much higher than in Opn4aDTA/aDTA mice, which leads to decreased innervation of the SCN during development. Using wheel-running activity, we show that Opn4DTA/DTA mice free-run with a significantly longer period than both wild type and Opn4aDTA/aDTA mice. We enucleated mice at P0 and in adulthood and show that a lengthened circadian period is recapitulated in mice enucleated at birth, indicating that ipRGCs are critical during development for the proper development of the circadian clock. Since ipRGCs are functional photoreceptors during development, we reared mice in constant darkness and found that mice that were never exposed to light also exhibit a lengthened circadian period. Strikingly, after exposure to light, mice that had been reared in constant darkness demonstrate a normal <24 hour intrinsic circadian period.
These data suggest light information relayed via ipRGCs is necessary during development for setting the intrinsic period of the circadian clock. Additionally, these results indicate that in the absence of light input, the circadian clock exhibits a lengthened circadian period and that this state remains plastic into adulthood.
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