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L.A. Owens, D.C. Tu, Y. Zhu, C.P. Fitzgerald, R.N. Van Gelder; Mutations in Circadian Clock Genes Reduce Behavioral and Pupillary Light Sensitivity of rd/rd Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5523.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal degenerate (rd/rd) mice lacking the circadian clock gene cryptochrome show reduced behavioral and pupillary light responsiveness compared with rd/rd mice. To determine the specificity of this effect, we sought to generate compound mutants of two other circadian clock genes – period and bmal1 – and rd/rd, and test these mice for circadian behavior, masking activity, and pupillary light responses.
Mice with mutations in the circadian clock genes cryptochromes1 and 2, period1 and 2, and bmal1 (cry1–/–; cry2–/–, per1–/–;per2–/–, and bmal1–/–) were studied with and without compounding to rd/rd mutation. C57BL/6 and rd/rd mice were used as controls. Light sensitivity in 4–8 month–old animals was assessed through behavioral means including activity rhythms, daily accumulations of running wheel counts, and pupillary responses. Electrical activity of whole retinas removed from 8–day old pups was also recorded on a multi–electrode array.
Free running circadian rhythms were absent in all three clock mutant strains. The three clock gene mutants showed some weak masking behavior. When compounded with the rd/rd mutation, all three mutants display a range of phenotype from weak masking to complete arrhythmicity. Masking phenotypes were worse in all clock mutants when compounded with rd/rd. Pupillary light responses from all clock genes are similar: the clock gene mutant alone is slightly less sensitive than wild–type while clock mutants compounded with rd/rd were significantly less sensitive than rd/rd alone. Pupillary light responses were found to have a significant circadian rhythm in rd/rd mice. Multi–electrode array recordings showed only slight loss of sensitivity of intrinsically photosensitivity retinal ganglion cells (ipRGCs) in clock gene mutants when compared to wild–type.
Loss of function of any of three circadian clock genes confers reduced behavioral and pupillary light responsiveness on rd/rd mice. The loss of sensitivity appears to occur downstream of ipRGC photoreception. These results demonstrate that the previously noted loss of light sensitivity in cryptochrome mutant mice is not specific for this strain.
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