Assessment of the Retina of Plp-α-Syn Mice as a Model for Studying Synuclein-Dependent Diseases

Abstract

PURPOSE. Synucleinopathies such as multiple system atrophy (MSA) and Parkinson's disease are associated with a variety of visual symptoms. Functional and morphological retinal aberrations are therefore supposed to be valuable biomarkers for these neurodegenerative diseases. This study examined the retinal morphology and functionality resulting from human α-synuclein (α-Syn) overexpression in the transgenic Plp-α-Syn mouse model. METHODS. Immunohistochemistry on retinal sections and whole-mounts was performed on 8-to 11-week-old and 12-month-old Plp-α-Syn mice and C57BL/6N controls. Quantitative RT-PCR experiments were performed to study the expression of endogenous and human α-Syn and tyrosine hydroxylase (TH). We confirmed the presence of human α-Syn in the retina in western blot analyses. Multi-electrode array (MEA) analyses from light-stimulated whole-mounted retinas were used to investigate their functionality. RESULTS. Biochemical and immunohistochemical analyses showed human α-Syn in the retina of Plp-α-Syn mice. We found distinct staining in different retinal cell layers, most abundantly in rod bipolar cells of the peripheral retina. In the periphery, we also observed a trend toward a decline in the number of retinal ganglion cells. The number of TH+ neurons was unaffected in this human α-Syn overexpression model. MEA recordings showed that Plp-α-Syn retinas were functional but exhibited mild alterations in dim light conditions. CONCLUSIONS. Together, these findings implicate an impairment of retinal neurons in the Plp-α-Syn mouse. The phenotype partly relates to retinal deficits reported in MSA patients. We further propose the suitability of the Plp-α-Syn retina as a biological model to study synuclein-mediated mechanisms.

Retinal and Brain Microglia in Multiple Sclerosis and Neurodegeneration

“…This suggests that there may be a differential expression of activated microglial markers and morphological changes through the early to intermediate stages of PD pathology. However, there are other studies that show that whilst there was OPL α-syn accumulation in mice modelled for α-syn-dependent diseases (Plp-α-syn), there were mostly ramified microglia found in whole-mounted retinal samples with no sign of microglial activation for all age groups investigated [113]. This may have been due to differences in disease models used, age groups investigated, and methods of analysis.…”

Knockout of CaV1.3 L-type calcium channels in a mouse model of retinitis pigmentosa

“…Glial fibrillary acidic protein (GFAP) is upregulated upon glial activation in the mouse retina 40 and constantly upregulated in rd10 mice in Müller cells 7 . Because GFAP accumulation is found in Müller cells of peripheral wild type retinas (and also in Cav1.3-KO, data not shown) unrelated to glial hyperreactivity 41 , we focused on the central retina of P45 mice. As shown in Fig.…”

Function of cone and cone-related pathways in CaV1.4 IT mice

“…Recordings were carried out with perforated 120-electrode micro-electrode arrays (MEA; 120pMEA100/30iR-Ti-pr, Multichannel Systems, Reutlingen, Germany). Experiments were performed as described 32 . Briefly, the dorsal retina was placed ganglion cell-side down in the recording chamber and continuously perfused with fresh bath solution at 30 °C.…”

“…Light stimulation was performed as described 32 . Briefly, a computer-controlled digital light processing projector (Lightcrafter E4500MKII, EKB Technologies Ltd, Bat Yam, Israel) was used to stimulate the retina with greyscale visual stimuli.…”