Abstract
Optic neuritis is one of the first manifestations of multiple sclerosis. Its pathogenesis is incompletely understood, but considered to be initiated by an auto‐immune response directed against myelin sheaths of the optic nerve. Here, we demonstrate in two frequently used and well‐validated mouse models of optic neuritis that ribbon synapses in the myelin‐free retina are targeted by an auto‐reactive immune system even before alterations in the optic nerve have developed. The auto‐immune response is directed against two adhesion proteins (CASPR1/CNTN1) that are present both in the paranodal region of myelinated nerves as well as at retinal ribbon synapses. This occurs in parallel with altered synaptic vesicle cycling in retinal ribbon synapses and altered visual behavior before the onset of optic nerve demyelination. These findings indicate that early synaptic dysfunctions in the retina contribute to the pathology of optic neuritis in multiple sclerosis.
Highlights
Multiple sclerosis (MS) is a frequent auto-immune inflammatory disease of the central nervous system (CNS)
Since we found a portion of CASPR1 and CNTN1 to be associated with retinal ribbon synapses in close vicinity to the synaptic ribbons in photoreceptor ribbon synapses, we asked whether this synaptic CASPR1/CNTN1 complex might be a neuroinflammatory target in mouse models of optic neuritis/MS
The starting point of our study was the finding that CASPR1 and CNTN1 are associated with synaptic ribbons in the retina
Summary
Multiple sclerosis (MS) is a frequent auto-immune inflammatory disease of the central nervous system (CNS). Most MS research focused on neuroinflammatory changes within the white matter of the brain, the spinal cord, and the optic nerves with myelin components considered as the primary immune target (Huang et al, 2017). Optic neuritis is a frequent manifestation of MS that is primarily attributed to an auto-immune response against components of the myelin sheath of the optic nerve. Except for retinal ganglion cells, the retina has not yet been considered as a primary immune target in MS or optic neuritis, effects on retinal layers distant from the retinal ganglion cell layer have been suggested by optical coherence tomography, a clinical imaging tool (Behbehani et al, 2017; Petzold et al, 2017). By antibody-based immunopurification of synaptic ribbon protein complexes using a monoclonal antibody against RIBEYE and by subsequent analysis of isolated protein complexes by mass spectrometry, we identified the adhesion proteins CASPR1 and contactin (CNTN1) as potential components associated with RIBEYE and the synaptic ribbon complex
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