Loss of complex gangliosides does not affect retinal structure and function in mice

Abstract

Purpose : Gangliosides (GGs) make a diverse family of glycosphingolipids localized primarily in the plasma membrane of mammalian cells and playing essential roles in cellular interactions and signaling. Especially abundant in the brain and nervous system, their implication in the development and integrity of these tissues is well described. While a few studies suggest the importance of GGs in the retina, their precise roles still need to be discovered. We aimed to characterize the retinal structure and function of a transgenic mouse model deficient in complex GGs, which are significantly expressed in the retina.

Methods : Aged GM2/GD2 synthase knock-out mice, a key enzyme for the biosynthesis of complex GGs, were used. Retina’s GG profile was determined by liquid chromatography coupled to mass spectrometry. The integrity of the retinal nervous cell types was evaluated by measuring the expression of specific genes using RT-qPCR. The number of retinal ganglion cells (RGCs) was evaluated by counting on flat-mounted retinas. The structural integrity of the retina was also investigated on cryosections by immunofluorescence. Retinal function was recorded by electroretinography. Finally, the response of the retina to an experimental optic neuropathy was studied.

Results : The retina of knock-out mice exhibited an altered GG profile characterized by a total lack of complex tetraosylGGs and increased levels of GD3 and its acetylated form, whose proportion increased by 2- and 10-fold, respectively, compared to wild-type mice. This did not significantly affect the integrity of the neural retina since the expression of specific markers of RGCs, photoreceptors and bipolar cells was unchanged, as was the number of RGCs per retina (around 35,000). Retinal cryosections did not show any abnormality in the distribution or morphology of the different cell types. Retinal functionality was similar between knock-out and wild-type mice. Finally, the extent of loss in RGC number (75%) and in expression of its specific markers (20 to 40% depending on the sex and marker considered) induced by the experimental model of optic neuropathy did not significantly vary between knock-out and wild-type mice.

Conclusions : Complex GGs related to GM2 / GD2 synthase do not seem to play a critical role in retinal structure and function in aged mice, likely due to redundancy in the functions of the different GGs.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.