{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:52:48Z","timestamp":1788385968974,"version":"build-2803163510"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>Huntington\u2019s disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction and cognitive decline. While retinal abnormalities have been documented in some HD patients and animal models, the nature of these abnormalities\u2014specifically whether they originate in the inner or outer retina\u2014remains unclear, particularly regarding their progression with age. This study investigates the retinal structure and function in HD transgenic mice (R6\/1) compared to C57BL\/6\u2009J control mice at 2, 4, and 6\u2009months of age, encompassing both pre-symptomatic and symptomatic stages of HD. Pathological assessments of the striatum and evaluations of motor function confirmed significant HD-related alterations in R6\/1 mice at 6\u2009months. Visual function was subsequently analyzed, accompanied by immunofluorescent staining of retinal and optic nerve tissues over time. Our findings revealed that R6\/1 mice exhibited pronounced HD symptoms at 6\u2009months, characterized by neuronal loss in the striatum and impaired locomotor abilities. Functionally, visual acuity declined at 6\u2009months, while retinal light responses began to deteriorate by 4\u2009months. Structurally, R6\/1 mice demonstrated a global reduction in cone opsin expression as early as 2\u2009months, with a decrease in rhodopsin levels at 4\u2009months, alongside a thinner retinal structure compared to controls. Notably, rod bipolar cell populations were decreased at 6\u2009months, exhibiting shorter dendritic branches and reduced synaptic connections with photoreceptors in the outer retina. Additionally, ganglion cell numbers in the inner retina decreased at 6\u2009months, accompanied by aberrant neural fibers in the optic nerve. Microglial activation was evident at 4\u2009months, while astrocytic activation was observed at 6\u2009months. Aggregates of mutant huntingtin (mHTT) were first detected in the ganglion cell layer and optic nerve at 2\u2009months, subsequently disseminating throughout all retinal layers with advancing age. These results indicate that retinal pathology in R6\/1 mice manifests earlier in the outer retina than in the inner retina, which does not align with the progression of mHTT aggregation. Consequently, the R6\/1 mouse retina may serve as a more effective model for elucidating the mechanisms underlying HD and evaluating potential therapeutic strategies, rather than functioning as an early diagnostic tool for the disease.<\/jats:p>","DOI":"10.3389\/fnagi.2024.1434551","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T04:45:25Z","timestamp":1730090725000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Abnormal outer and inner retina in a mouse model of Huntington\u2019s disease with age"],"prefix":"10.3389","volume":"16","author":[{"given":"Dashuang","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemeng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yintian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaijun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1136\/jnnp-2022-329342","article-title":"Structural and functional changes in the retina in Parkinson\u2019s disease","volume":"94","author":"Alves","year":"2023","journal-title":"J. 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Is optical coherence tomography a good biomarker?","volume":"18","author":"Dusek","year":"2023","journal-title":"PLoS One"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1212\/wnl.28.1.95","article-title":"The visually evoked potential in Huntington disease","volume":"28","author":"Ellenberger","year":"1978","journal-title":"Neurology"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1007\/s10792-018-0857-7","article-title":"Retinal single-layer analysis with optical coherence tomography shows inner retinal layer thinning in Huntington\u2019s disease as a potential biomarker","volume":"39","author":"Gulmez Sevim","year":"2019","journal-title":"Int. Ophthalmol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3351","DOI":"10.1093\/hmg\/11.26.3351","article-title":"Progressive retinal degeneration and dysfunction in R6 Huntington\u2019s disease mice","volume":"11","author":"Helmlinger","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/0168-5597(85)90011-5","article-title":"Evoked potentials in patients with Huntington\u2019s disease and their offspring. II. Visual evoked potentials","volume":"62","author":"Hennerici","year":"1985","journal-title":"Electroencephalogr. Clin. Neurophysiol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"113443","DOI":"10.1016\/j.celrep.2023.113443","article-title":"Comparing HD knock-in pigs and mice reveals the pathological role of IL-17","volume":"42","author":"Jia","year":"2023","journal-title":"Cell Rep."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"a024240","DOI":"10.1101\/cshperspect.a024240","article-title":"Huntington\u2019s disease: mechanisms of pathogenesis and therapeutic strategies","volume":"7","author":"Jimenez-Sanchez","year":"2017","journal-title":"Cold Spring Harb. Perspect. 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Ophthalmol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"2290","DOI":"10.4103\/1673-5374.390958","article-title":"Lycium barbarum glycopeptide (wolfberry extract) slows N-methyl-N-nitrosourea-induced degradation of photoreceptors","volume":"19","author":"Kong","year":"2024","journal-title":"Neural Regen. Res."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/s0092-8674(00)81369-0","article-title":"Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice","volume":"87","author":"Mangiarini","year":"1996","journal-title":"Cell"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"5450","DOI":"10.3390\/ijms23105450","article-title":"Structural abnormalities of the optic nerve and retina in Huntington\u2019s disease pre-clinical and clinical settings","volume":"23","author":"Mazur-Micha\u0142ek","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.3390\/cells11101675","article-title":"Identification of the transcriptional biomarkers panel linked to pathological Remodelling of the eye tissues in various HD mouse models","volume":"11","author":"Mazur-Micha\u0142ek","year":"2022","journal-title":"Cells"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1016\/0013-4694(81)90211-x","article-title":"Visual (VEP) and somatosensory (SSEP) evoked potentials in Huntington\u2019s chorea","volume":"51","author":"Oepen","year":"1981","journal-title":"Electroencephalogr. Clin. Neurophysiol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1038\/sj.mt.6300185","article-title":"Expression of mutated huntingtin fragment in the putamen is sufficient to produce abnormal movement in non-human Primates","volume":"15","author":"Palfi","year":"2007","journal-title":"Mol. Ther."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"237","DOI":"10.3233\/JHD-170255","article-title":"Enhanced retinal responses in Huntington\u2019s disease patients","volume":"6","author":"Pearl","year":"2017","journal-title":"J. Huntingt. Dis."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"eadl2036","DOI":"10.1126\/sciadv.adl2036","article-title":"TRIM37 is a primate-specific E3 ligase for huntingtin and accounts for the striatal degeneration in Huntington\u2019s disease","volume":"10","author":"Qin","year":"2024","journal-title":"Sci. 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