Bedeutung synaptischer Pathologie für Neurodegeneration bei der autoimmunen Optikusneuritis
Zusammenfassung der Projektergebnisse
Synaptic dysfunction is becoming increasingly understood to be a common early event in the process of neurodegeneration, as seen in various diseases from prion disorders, Alzheimer’s disease, and Huntington’s disease. To date, the contribution of synaptic pathology to the neurodegeneration occurring during the development of autoimmune disorders such as optic neuritis has not been addressed. In an animal model of autoimmune optic neuritis, the presence of synaptic loss is suggested by not only the neuronal decline observed during the preclinical induction period of the disease occurring shortly following immunisation with myelin oligodendrocyte glycoprotein (MOG), but also the decay in visually-evoked potentials, suggesting that damage to the connectivity between the retina and the higher brain areas involved in processing visual information is present. To determine whether a functional or structural disruption in retinal ganglion cell synapses is occurring, this study has employed histopathological, ultrastructural and electrophysiological methods to assess synaptic integrity. In the superior colliculus, where retinal ganglion cells project their axons and make synaptic contact with neurons of the brain, no large-scale changes in synaptic protein levels or localisation was seen. However, upon analysing the ultrastructure of synapses within this region, a trend was seen towards both a reduction in synaptic density and the number of docked vesicles at the presynaptic active zone already during the preclinical period, becoming significant as the clinical disease began (approximately 14 days post immunisation). Functionally, the amplitude of evoked excitatory presynaptic currents was significantly reduced by day 10 post immunisation, several days before disease onset. Thus, a disruption in normal synaptic function appears to be an early event during the onset of optic neuritis. We hypothesise that disrupted axonal trafficking along the optic nerve may result in reduced availability of vesicles or the machinery necessary for correct docking of vesicles. This may be more apparent within the superior colliculus due to the long transport distances from the retinal cell bodies to their presynaptic terminals, and also due to the susceptibility of the retina and the myelinated tracts of the optic nerve to inflammatory attack following MOG immunisation. Further research is necessary to confirm the structural underpinnings of the early synaptic dysregulation reported here, and to determine novel therapeutic strategies for protecting against synaptic loss during the preclinical period.
