Attenuated pupillary light responses and downregulation of opsin expression parallel decline in circadian disruption in two different mouse models of Huntington's disease
Human Molecular Genetics
Oxford University Press
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Ouk, K., Hughes, S., Pothecary, C., Peirson, S., & Morton, J. (2016). Attenuated pupillary light responses and downregulation of opsin expression parallel decline in circadian disruption in two different mouse models of Huntington's disease. Human Molecular Genetics, 25 5418-5432. https://doi.org/10.1093/hmg/ddw359
Circadian deficits in Huntington’s disease (HD) are recapitulated in both fragment (R6/2) and full-length (Q175) mouse models of HD. Circadian rhythms are regulated by the suprachiasmatic nuclei (SCN) in the hypothalamus, which are primarily entrained by light detected by the retina. The SCN receives input from intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment melanopsin, but also receive input from rods and cones. In turn, ipRGCs mediate a range of non-image forming responses to light including circadian entrainment and the pupillary light response (PLR). Retinal degeneration/dysfunction has been described previously in R6 /2 mice. We investigated, therefore, whether or not circadian disruption in HD mice is due to abnormalities in retinal photoreception. We measured expression of melanopsin, rhodopsin and cone opsin, as well as other retinal markers (tyrosine hydroxylase, calbindin, PKCα and Brna3 ), in R6/2 and Q175 mice at different stages of disease. We also measured the PLR as a ‘readout’ for ipRGC function and a marker of light reception by the retina. We found that the PLR was attenuated in both lines of HD mice. This was accompanied by a progressive downregulation of cone opsin and melanopsin expression. We suggest that a disease-related change in photoreception by the retina contributes to the progressive dysregulation of circadian rhythmicity and entrainment seen in HD mice. Colour vision is abnormal in HD patients. Therefore, if retinal deficits similar to those seen in HD mice are confirmed in patients, specifically designed light therapy may be an effective strategy to improve circadian dysfunction.
This work was supported by a grant from CHDI (Inc.) to AJM. SH is funded by a BBSRC grant (BB/M009998/1). SNP and CAP are funded by a Wellcome Trust strategic grant (098461/Z/12/Z).
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External DOI: https://doi.org/10.1093/hmg/ddw359
This record's URL: https://www.repository.cam.ac.uk/handle/1810/261678