Very long-chain fatty acids support synaptic structure and function in the mammalian retina

Abstract

-Elongation of Very Long chain fatty acids-like 4 (ELOVL4) is a fatty acid elongase responsible for the biosynthesis of very long chain (VLC; ≥ C26) fatty acids in the retina, brain, skin, Meibomian gland, and testes. Heterozygous inheritance of mutant ELOVL4 causes juvenile macular degeneration in autosomal dominant Stargardt-like macular dystrophy (STGD3). Retinal photoreceptors are enriched with VLC polyunsaturated fatty acids (VLC-PUFAs), which have been shown by our group and others to be necessary for the survival of rod photoreceptors. Our group performed a series of studies using mice conditionally depleted of retinal Elovl4 (KO) aimed at understanding the role of VLC-PUFAs in long-term retinal health and function, focusing on the role of these fatty acids in mediating synaptic function between the photoreceptors and the rest of the neural retina. The absence of VLC-PUFA from the retina of KO mice resulted in a marked decrease in retinal b-wave responses of the electroretinogram as well as a decrease in the amplitude of the oscillatory potentials mediated by the neural retina. Although there were no measureable differences between KO and wild type (WT) mice in either pre-synaptic rod calcium channel function or post-synaptic bipolar cell glutamate receptor responses, ultrastructural analysis revealed a marked decrease in the diameter of synaptic vesicles in rod terminals. Recent quantification suggests that this decrease in synaptic vesicle size due to the absence of VLC-PUFAs in KO mice, and the consequent decrease in glutamate content, could account for the decrease in b-wave response amplitudes that were previously measured in these animals.Keywords: ELOVL4 / very long chain fatty acids / very long chain polyunsaturated fatty acids / Stargardt-like macular dystrophy / Lipids in retinal structure and function Résumé -Les acides gras à très longue chaîne participent à la structure et à la fonction synaptique dans la rétine des mammifères. L'ELOVL4 (elongation of very long chain fatty acids-like 4) est une élongase d'acide gras impliquée spécifiquement dans la voie de biosynthèse d'acides gras à très longue chaîne (VLC de longueur de chaîne ≥ 26 atomes de carbone) dans la rétine, le cerveau, la peau, la glande de Meibomius (glande sébacée située dans l'épiderme des paupières) et les testicules. La transmission de la mutation hétérozygote ELOVL4 provoque une dégé-nérescence maculaire juvénile dans la dystrophie maculaire autosomique dominante de type Stargardt (STGD3). Les photorécepteurs rétiniens sont enrichis en acides gras polyinsaturés à très longue chaîne (AGPI-VLC), qui s'avèrent nécessaires à la survie des photorécepteurs en bâtonnet. Afin de mieux comprendre le rôle spécifique de ces acides gras dans le fonctionnement rétinien et à plus long terme la santé, notre groupe de recherche a effectué une série d'études utilisant des souris génétiquement dépourvues (KO) en ELOVL4 rétinienne, en se concentrant sur la mé-diation de la fonction synaptique entre les photorécepteurs et le reste de la...

ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function

“…Because volume scales with the cube of radius, this relatively small change in diameter would result in a reduction in volume, and thus glutamate content, of ~57%–43% of control. This reduction in glutamate content may explain the 50% decrease in b-wave amplitude in Chx10-cKO mice (Bennett et al, 2014b; Hopiavuori et al, 2016). Therefore, it is likely that the decreased presynaptic vesicle size and number resulted in decreased synaptic efficiency and drove the reorganization of the rod terminals and the bipolar dendrites within the OPL, as was observed (Bennett et al, 2014b).…”

“…This unique combination provides fluid-like properties to the lipid bilayer. In bovine retina, VLC-PUFA are enriched in rod photoreceptor outer segments (OS) (Aveldano, 1987; Aveldano and Sprecher, 1987; Martin et al, 2005), as well as in both large ribbon synapses and smaller conventional synapses (Bennett et al, 2014b; Hopiavuori et al, 2016). The increased fluidity of OS membranes, in part due to their high VLC-PUFA content, is favorable and may assist in photoreceptor disc migration and OS shedding to the retina pigment epithelium (RPE).…”

“…In tying these findings in brain back to the retina, we have proposed the hypothesis that the loss of synaptic vesicle number and changes in structural morphology in Chx10-cKO mice (Bennett et al, 2014b) is likely a consequence of VLC-FA deficiency in these specialized membranes (Hopiavuori et al, 2016). This hypothesis is supported in part by a recent report (Donato et al, 2018b) showing that expression of the c.−90 G > C or c. −236 C > T variants, and co-expression of the c. −90 G > C and c. −236 C > T ELOVL4 variants, in the promoter region of ELOVL4, cause downregulation of ELOVL4 activity.…”

“…Post-synaptic glutamatergic currents mediated by mGluR6 were measured and no significant differences were detected between WT and Chx10-cKO mice, indicating that changes in the b-wave were not mediated by dysregulation of post-synaptic glutamate currents. A lack of significant differences between WT and Chx10-cKO mice in both pre-synaptic ICa 2+ and postsynaptic rod bipolar cell glutamate receptor currents indicates that the decrease in synaptic transmission is most likely due to deficits in pre-synaptic release downstream of ICa 2+ , but upstream of post-synaptic metabotropic glutamate receptor responses (Hopiavuori et al, 2016). A critical observation is that the diameters of synaptic vesicles from Chx10-cKO mice were significantly smaller than those from WT mice, 24.5 nm vs. 29.5 nm, respectively (Bennett et al, 2014b).…”

Remodeling of Membrane Shape and Topology by Curvature Elasticity and Membrane Tension

“…In addition, the eukaryotic cells of animals and plants contain a large number of intracellular membranes that enclose different organelles as in Figure 1. The cellular membranes differ greatly in their lateral extensions, from many tens of micrometers for plasma membranes to small nanovesicles such as synaptic vesicles with a diameter that varies between 20 and 50 nm [ 18,19 ] as well as exosomes, which represent small extracellular vesicles with a diameter between 25 and 100 nm. [ 20–22 ] In recent years, exosomes and somewhat larger extracellular vesicles have been intensely studied as possible biomarkers for diseases and as targeted drug delivery systems.…”