Abstract
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that finally leads to demyelination. Demyelinating optic neuritis is a frequent symptom in MS. Recent studies also revealed synapse dysfunctions in MS patients and MS mouse models. We previously reported alterations of photoreceptor ribbon synapses in the experimental auto-immune encephalomyelitis (EAE) mouse model of MS. In the present study, we found that the previously observed decreased imunosignals of photoreceptor ribbons in early EAE resulted from a decrease in synaptic ribbon size, whereas the number/density of ribbons in photoreceptor synapses remained unchanged. Smaller photoreceptor ribbons are associated with fewer docked and ribbon-associated vesicles. At a functional level, depolarization-evoked exocytosis as monitored by optical recording was diminished even as early as on day 7 after EAE induction. Moreover compensatory, post-depolarization endocytosis was decreased. Decreased post-depolarization endocytosis in early EAE correlated with diminished synaptic enrichment of dynamin3. In contrast, basal endocytosis in photoreceptor synapses of resting non-depolarized retinal slices was increased in early EAE. Increased basal endocytosis correlated with increased de-phosphorylation of dynamin1. Thus, multiple endocytic pathways in photoreceptor synapse are differentially affected in early EAE and likely contribute to the observed synapse pathology in early EAE.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to axonal demyelination and glial scars in the white matter [1,2,3,4]
In a previous study [24], we showed that RIBEYE immunosignals were decreased in rod photoreceptor synapses of EAE mice at an early pre-clinical stage
In a previous study [24], we found that the RIBEYE immunosignals of rod photoreceptor synaptic ribbons in the outer plexiform layer (OPL) were significantly weaker in early EAE mice in comparison to photoreceptor synaptic ribbons from the CFA-injected control group
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to axonal demyelination and glial scars in the white matter [1,2,3,4]. Synapse alterations occurred in the pre-clinical phase even before the onset of optic nerve demyelination both in MS patients as well as in the EAE mouse model [7,24,25]. In a previous study [24], we showed that RIBEYE immunosignals were decreased in rod photoreceptor synapses of EAE mice at an early pre-clinical stage. We sought to determine the reason for the decreased RIBEYE immunosignals in rod photoreceptor ribbon synapses of EAE mice at the early pre-clinical stage. The decrease in synaptic ribbon size in rod synapses is accompanied by a decrease in depolarization-evoked synaptic vesicle exocytosis (as early as on day 7 after injection) and by a decrease in post-stimulus vesicle endocytosis. In contrast to the decreased evoked responses, basal vesicle cycling under resting conditions was elevated in early EAE photoreceptors, most likely resulting from elevated basal presynaptic Ca2+ levels that were recently identified [25]
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