Degeneration of ipRGCs in Mouse Models of Huntington's Disease Disrupts Non-Image-Forming Behaviors Before Motor Impairment

Abstract

Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin, are photosensitive neurons in the retina and are essential for non-image-forming functions, circadian photoentrainment, and pupillary light reflexes. Five subtypes of ipRGCs (M1-M5) have been identified in mice. Although ipRGCs are spared in several forms of inherited blindness, they are affected in Alzheimer's disease and aging, which are associated with impaired circadian rhythms. Huntington's disease (HD) is an autosomal neurodegenerative disease caused by the expansion of a CAG repeat in the huntingtin gene. In addition to motor function impairment, HD mice also show impaired circadian rhythms and loss of ipRGC. Here, we found that, in HD mouse models (R6/2 and N171-82Q male mice), the expression of melanopsin was reduced before the onset of motor deficits. The expression of retinal T-box brain 2, a transcription factor essential for ipRGCs, was associated with the survival of ipRGCs. The number of M1 ipRGCs in R6/2 male mice was reduced due to apoptosis, whereas non-M1 ipRGCs were relatively resilient to HD progression. Most importantly, the reduced innervations of M1 ipRGCs, which was assessed by X-gal staining in R6/2-OPN4 Lacz/ϩ male mice, contributed to the diminished light-induced c-fos and vasoactive intestinal peptide in the suprachiasmatic nuclei (SCN), which may explain the impaired circadian photoentrainment in HD mice. Collectively, our results show that M1 ipRGCs were susceptible to the toxicity caused by mutant Huntingtin. The resultant impairment of M1 ipRGCs contributed to the early degeneration of the ipRGC-SCN pathway and disrupted circadian regulation during HD progression.Circadian disruption is a common nonmotor symptom of Huntington's disease (HD). In addition to the molecular defects in the suprachiasmatic nuclei (SCN), the cause of circadian disruption in HD remains to be further explored. We hypothesized that ipRGCs, by integrating light input to the SCN, participate in the circadian regulation in HD mice. We report early reductions in melanopsin in two mouse models of HD, R6/2, and N171-82Q. Suppression of retinal T-box brain 2, a transcription factor essential for ipRGCs, by mutant Huntingtin might mediate the reduced number of ipRGCs. Importantly, M1 ipRGCs showed higher susceptibility than non-M1 ipRGCs in R6/2 mice. The resultant impairment of M1 ipRGCs contributed to the early degeneration of the ipRGC-SCN pathway and the circadian abnormality during HD progression.

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis

“…Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin, are photosensitive neurons in the retina and are essential for circadian synchronization (e.g., Schmidt, Chen, & Hattar, ). Five subtypes of ipRGCs (M1–M5) have been identified in mice and recent work suggests that the M1 subtype is reduced in other HD models (R6/2 and N171‐82Q) prior to the onset of motor deficits (Lin et al, ; Ouk, Hughes, Pothecary, Peirson, & Morton, ). The reduced innervation of M1 ipRGCs is likely to contribute to a diminished light‐induction of c‐fos in the central clock, the suprachiasmatic nucleus (SCN), which may explain the impaired circadian light response in these HD mice.…”

Melanopsin+RGCs Are fully Resistant to NMDA-Induced Excitotoxicity

“…For example, recent studies using genetic markers to identify different types of RGCs have shown that the type of αRGC is particularly resistant to NMDA induced neurotoxicity [8] or to optic nerve crush [35,39], in contrast to the very low survival of junction adhesion molecules B-expressing RGCs (J-RGCs) [8]. Moreover, recent studies indicate that different subtypes of ipRGCs have different susceptibility to specific insults; for instance, in a mouse model of Huntington’s disease (HD), M1 were reduced compared to non-M1 ipRGCs that survived to HD progression [112]. Furthermore, in a mouse model of ocular hypertension, subtypes of αRGCs were found to have different susceptibility, with OFF-transient αRGCs being more vulnerable than ON- or OFF-sustained αRGCs [22,73].…”

Abnormal Photic Entrainment to Phase-Delaying Stimuli in the R6/2 Mouse Model of Huntington's Disease, despite Retinal Responsiveness to Light

“…The SCN synchronizes to the LD of the environment through the action of light received by the light-sensitive retinal ganglion cells (Panda et al, 2002;Ruby et al, 2002). Both R6/2 and Q175 mice-a HD model with slower phenotype development-exhibit progressive retinal morphologic changes, including a downregulation in the expression of melanopsin and cone opsin, markers of retinal light-sensitive and cone cells, respectively (Ouk et al, 2016b;Lin et al, 2019). Photodetection appeared to be progressively impaired in R6/2 mice because they exhibited attenuation in their PLR from 12 weeks of age for light at low intensity.…”

“…In addition to a complex set of progressive motor, cognitive, and psychiatric symptoms (Bates et al, 2015;Schobel et al, 2017), HD is characterized by a progressive disruption in sleep and circadian rhythms (Aziz et al, 2010;Morton, 2013;van Wamelen et al, 2015). The circadian disruption is recapitulated in multiple mouse models of HD (Morton et al, 2005;Kudo et al, 2011;Lin et al, 2019), including the R6/2 mouse used in this study. Although the circadian disruption observed in R6/2 mice is accompanied at a molecular level by a dysregulation of the clock genes expression in the SCN (Morton et al, 2005), the molecular machinery in the SCN remains functionally intact (Pallier et al, 2007).…”