Attenuated pupillary light responses and downregulation of opsin expression parallel decline in circadian disruption in two different mouse models of Huntington's disease.

Koliane Ouk,Stuart N Peirson,Steven Hughes,A Jennifer Morton,Carina A Pothecary

doi:10.1093/hmg/ddw359

Koliane Ouk, Stuart N Peirson + Show 3 more

Open Access

https://doi.org/10.1093/hmg/ddw359

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Abstract

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 the 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 disease-related changes in photoreception by the retina contribute 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.

Highlights

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an abnormal CAG expansion in the HD gene [1]
At 9 weeks, there was already a significant effect of genotype on pupillary light response (PLR) [F(1,37) 1⁄4 6.73, P < 0.05; Fig. 1A], with presymptomatic R6/2 mice showing an attenuation of their response to light under low irradiance at 11.6 log quanta/cm2/s compared to wild type (WT) mice (P < 0.01)
Post hoc analysis revealed that the attenuation in PLR seen earlier at 11.6 log quanta/cm2/s compared to WT mice was maintained at 12 weeks (P < 0.01)

Summary

Introduction

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an abnormal CAG expansion in the HD gene [1]. Given the prominent role of melanopsin ipRGCs in mediating circadian photoentrainment, we investigated whether progressive neurodegeneration of ipRGCs, loss of the rod or cone inputs, or loss of function of melanopsin contribute to the progressive dysregulation of circadian rhythmicity and impairment of photic synchronization in HD Such loss may contribute to abnormal circadian entrainment phenotype (such as that seen in HD mice), whereas loss of all photoreception from the retina would result in free-running rather than arrhythmia or rhythm fragmentation. We assessed the expression of key photopigments (melanopsin, ultraviolet sensitive (UVS) and middle-wave sensitive (MWS) cone opsins and rhodopsin), markers of other retinal cell types (tyrosine hydroxylase (TH), calbindin, Brain-specific homeobox/POU domain protein 3a (Brn3a) and protein kinase C alpha (PKCa)) and we examined the occurrence of huntingtin (Htt) depositions (using MW8), in retina from R6/2 and Q175 mice at different stages of the disease

Results

Discussion

Materials and Methods