Defective ceramide synthases in mice cause reduced amplitudes in electroretinograms and altered sphingolipid composition in retina and cornea

Abstract

Complex sphingolipids are strongly expressed in neuronal tissue and contain ceramides in their backbone. Ceramides are synthesized by six ceramide synthases (CerS1-6). Although it is known that each tissue has a unique profile of ceramide synthase expression and ceramide synthases are implicated in several neurodegenerative disorders, the expression of ceramide synthase isoforms has not been investigated in the retina. Here we demonstrate CerS1, CerS2 and CerS4 expression in mouse retina and cornea, with CerS4 ubiquitously expressed in all retinal neurons and Müller cells. To test whether ceramide synthase deficiency affects retinal function, we compared electroretinograms and retina morphology between wild-type and CerS1-, CerS2- and CerS4-deficient mice. Electroretinograms were strongly reduced in amplitude in ceramide synthase-deficient mice, suggesting that signalling in the outer retina is affected. However, the number of photoreceptors and cone outer segment length were unaltered and no changes in retinal layer thickness or synaptic structures were found. Mass spectrometric analyses of ceramides, hexosyl-ceramides and sphingomyelins showed that C20 to C24 acyl-containing species were decreased whereas C16-containing species were increased in the retina of ceramide synthase-deficient mice. Similar but smaller changes were also found in the cornea. Thus, we hypothesize that the replacement of very long-chain fatty acyl residues by shorter C16 residues may affect the electrical properties of retina and cornea, and alter receptor-mediated signal transduction, vesicle-mediated synaptic transmission or corneal light transmission. Future studies need to identify the molecular targets of ceramides or derived sphingolipids in light signal transduction and transmission in the eye.

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

“…16,53 Decreased ERG amplitude has also been documented in mice deficient in acid sphingomyelinase, hexosaminidase, and ceramide synthases 1, 2, and 4. 17,18,54 The similarities in disease manifestations seen in these reports and our current study suggest that insults to sphingolipid metabolism lead to comparable pathologies because homeostatic control of sphingolipids is tightly regulated.…”

Alteration of Sphingolipids in Biofluids: Implications for Neurodegenerative Diseases

“…Moreover, a specific cell type expression was shown, with neurons presenting higher CerS1 expression, while CerS2 was predominantly expressed in myelinating cells of mouse brains [17]. In mouse retina, expression of CerS1, CerS2, and CerS4 was detected, with CerS4 expressed in all retinal neurons and Müller cells [18].…”

Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

“…In the cornea, CerS1 and CerS4 are weakly present, whereas CerS2 is strongly expressed. CerS4 is ubiquitously expressed in all retinal neurons (photoreceptors, especially cones, horizontal cells, ON and OFF bipolar cells, GABAergic amacrine cells, ganglion cells) and in Muller glia [89]. In the optic nerve, immunofluorescent reaction on CerS2 was found in the somata of oligodendrocytes, but not along myelinated axons or their myelins' heath outside of oligodendrocyte somata [90].…”

“…All CerS-deficient mice showed reduced electroretinogram amplitudes, with the most severe phenotype in CerS2 knockout (KO) mice, but had normal retinal morphology. CerS-deficient mice showed altered sphingolipid composition in the retina; moreover, retinal C16-sphingomyelins levels were elevated while C18-sphingomyelins levels were reduced [89]. Inhibition of ceramide synthesis by the sphingosine analog FTY720 protects rat retina from light-induced degeneration [97].…”