Loss of retinal ganglion cells in a new genetic mouse model for primary open‐angle glaucoma

Abstract

Primary open‐angle glaucoma (POAG) is one of the most common causes for blindness worldwide. Although an elevated intraocular pressure (IOP) is the main risk factor, the exact pathology remained indistinguishable. Therefore, it is necessary to have appropriate models to investigate these mechanisms. Here, we analysed a transgenic glaucoma mouse model (βB1‐CTGF) to elucidate new possible mechanisms of the disease. Therefore, IOP was measured in βB1‐CTGF and wildtype mice at 5, 10 and 15 weeks of age. At 5 and 10 weeks, the IOP in both groups were comparable ( P > 0.05). After 15 weeks, a significant elevated IOP was measured in βB1‐CTGF mice ( P < 0.001). At 15 weeks, electroretinogram measurements were performed and both the a‐ and b‐wave amplitudes were significantly decreased in βB1‐CTGF retinae (both P < 0.01). Significantly fewer Brn‐3a + retinal ganglion cells (RGCs) were observed in the βB1‐CTGF group on flatmounts ( P = 0.02), cross‐sections ( P < 0.001) and also via quantitative real‐time PCR ( P = 0.02). Additionally, significantly more cleaved caspase 3 + RGCs were seen in the βB1‐CTGF group ( P = 0.002). Furthermore, a decrease in recoverin + cells was observable in the βB1‐CTGF animals ( P = 0.004). Accordingly, a significant down‐regulation of Recoverin mRNA levels were noted ( P < 0.001). Gfap expression, on the other hand, was higher in βB1‐CTGF retinae ( P = 0.023). Additionally, more glutamine synthetase signal was noted ( P = 0.04). Although no alterations were observed regarding photoreceptors via immunohistology, a significant decrease of Rhodopsin ( P = 0.003) and Opsin mRNA ( P = 0.03) was noted. We therefore assume that the βB1‐CTGF mouse could serve as an excellent model for better understanding the pathomechanisms in POAG.

Intravitreal Therapy Against the Complement Factor C5 Prevents Retinal Degeneration in an Experimental Autoimmune Glaucoma Model

“…Nevertheless, in late stages, a degeneration of photoreceptor cells was reported via ERG in glaucoma patients (Nork et al, 2000; Velten et al, 2001). Additionally, in different OHT animal models, an impairment of photoreceptors was noted (Heiduschka et al, 2010; Ortin-Martinez et al, 2015; Reinehr et al, 2019). The mild differences of the a-wave amplitude in our EAG model were accompanied by a loss of L-opsin + cells and a downregulation of Rho mRNA levels in the ONA group.…”

“…For example, OHT induction led to a diminished immunoreactivity of recoverin (Cuenca et al, 2010). Also in the βB1-CTGF mice, a model for POAG, fewer recoverin cells were observed (Reinehr et al, 2019). The functional loss of the b-wave amplitude was accompanied by fewer recoverin + cone bipolar cells in ONA retinas compared to controls in the study presented here.…”

Rotenone-induced inner retinal degeneration via presynaptic activation of voltage-dependent sodium and L-type calcium channels in rats

“…Rotenone injection dose-dependently reduced the expression of parvalbumin gene (Pvalb), but not tyrosine hydroxylase (Th), which are markers for amacrine cells 20,21 . For bipolar cells, rotenone slightly increased metabotropic glutamate receptor 6 gene (Grm6) expression 21 , whereas it did not alter protein kinase C alpha gene (Prkca) expression 21,22 . The photoreceptor marker opsin 1 gene, short-wave-sensitive (Opn1sw) expression 22 , but not rhodopsin (Rho) 20,22 , was also reduced.…”

“…For bipolar cells, rotenone slightly increased metabotropic glutamate receptor 6 gene (Grm6) expression 21 , whereas it did not alter protein kinase C alpha gene (Prkca) expression 21,22 . The photoreceptor marker opsin 1 gene, short-wave-sensitive (Opn1sw) expression 22 , but not rhodopsin (Rho) 20,22 , was also reduced. Taken together, Nfl expression represents rotenone-induced inner retinal degeneration, and can be used as a surrogate marker for further pharmacological analysis.…”

Glaukom im Fokus

“…In diesen Tieren kommt es durch die Überexpression von CTGF zu einer Versteifung des Aktins im Trabekelmaschenwerk. Dies führt zu einem erhöhten IOD und einer Degeneration der retinalen Ganglienzellen in 15 Wochen alten CTGF-Mäusen [9]. Nachfolgende Analysen des Komplementsystems wurden bei 5, 10 und 15 Wochen alten CTGF-Tieren und den entsprechenden Kontrollen durchgeführt.…”