Structural Changes and Astrocyte Response of the Lateral Geniculate Nucleus in a Ferret Model of Ocular Hypertension

Abstract

We investigated structural changes and astrocyte responses of the lateral geniculate nucleus (LGN) in a ferret model of ocular hypertension (OH). In 10 ferrets, OH was induced via the injection of cultured conjunctival cells into the anterior chamber of the right eye; six normal ferrets were used as controls. Anterograde axonal tracing with cholera toxin B revealed that atrophic damage was evident in the LGN layers receiving projections from OH eyes. Immunohistochemical analysis with antibodies against NeuN, glial fibrillary acidic protein (GFAP), and Iba-1 was performed to specifically label neurons, astrocytes, and microglia in the LGN. Significantly decreased NeuN immunoreactivity and increased GFAP and Iba-1 immunoreactivities were observed in the LGN layers receiving projections from OH eyes. Interestingly, the changes in the immunoreactivities were significantly different among the LGN layers. The C layers showed more severe damage than the A and A1 layers. Secondary degenerative changes in the LGN were also observed, including neuronal damage and astrocyte reactions in each LGN layer. These results suggest that our ferret model of OH is valuable for investigating damages during the retina–brain transmission of the visual pathway in glaucoma. The vulnerability of the C layers was revealed for the first time.

Transneuronal Degeneration in the Brain During Glaucoma

“…In addition to the glaucoma monkey model, researchers have constructed an experimental ferret model of high intraocular pressure to analyze the central damage of glaucoma (Fujishiro et al, 2014 ). In this model, Fujishiro et al also found damage to the LGN, but, again, there was no priority pathway in terms of one cell type experiencing more damage than the other (Fujishiro et al, 2020 ).…”

“…It was found that NeuN, glial fibrillary acidic protein (GFAP) and Iba-1 immunoreactivity increased was observed in the LGN layer receiving OH eye projection. In addition, the results also showed that the damage to layer C was greatest, suggesting that the W cells projected to layer C were more sensitive and vulnerable to OH-induced neuronal damage than the X and Y cells projected to An and A1 layers (Fujishiro et al, 2020 ). However, the mechanism behind the damage to the K cells of primates and humans with glaucoma, needs to be further explored.…”

Structural and functional plasticity in the dorsolateral geniculate nucleus of mice following bilateral enucleation

“…We found that microglia density in the dLGN increases with enucleation and those microglia display morphological features indicative of activation, including reduction in process length and number of process endpoints. There is evidence for microglia activation in the dLGN in experimental glaucoma and inflammatory demyelinating disease (Tribble et al, 2021; Fujishiro et al, 2020; Lam et al, 2009; Araujo et al, 2017). Although enucleation is a much more rapid and extreme axonal injury than typical glaucoma, our findings might recapitulate some of the pathological events of glaucoma or other optic neuropathies, albeit on an accelerated time course.…”

Therapeutic Drugs and Devices for Tackling Ocular Hypertension and Glaucoma, and Need for Neuroprotection and Cytoprotective Therapies

“…Adding insult to injury, the increased tortoucity of the RGC axons causes disruption of the axonal transport of growth factors and mitochondria from the brain back to the RGC bodies (Dengler- Crish et al, 2014;Fahy et al, 2016). The inflammatory and immunologic insults on the optic nerve components induces a dislocation of the RGC axonal terminal connections to the thalamic LGN and pretectal regions of the brain (Dai et al, 2012;Ghaffarieh and Levin, 2012;Fujishiro et al, 2020) with ensuing retrograde atrophy of the RGC axons and neuronal loss in the LGN (Yucel et al, 2000;Yucel et al, 2001;Gupta et al, 2007). Dropout of RGC axons thins the optic nerve and the RNFL at the ONH.…”