Abstract
Axo-glial units are highly organised microstructures propagating saltatory conduction and are disrupted during multiple sclerosis (MS). Nogo receptor 1 (NgR1) has been suggested to govern axonal damage during the progression of disease in the MS-like mouse model, experimental autoimmune encephalomyelitis (EAE). Here we have identified that adult ngr1−/− mice, previously used in EAE and spinal cord injury experiments, display elongated paranodes, and nodes of Ranvier. Unstructured paranodal regions in ngr1−/− mice are matched with more distributed expression pattern of Caspr. Compound action potentials of optic nerves and spinal cords from naïve ngr1−/− mice are delayed and reduced. Molecular interaction studies revealed enhanced Caspr cleavage. Our data suggest that NgR1 may regulate axo-myelin ultrastructure through Caspr-mediated adhesion, regulating the electrophysiological signature of myelinated axons of central nervous system (CNS).
Highlights
Myelination ensures that action potentials are propagated along axons effectively
As axonal diameter has been shown to regulate the structure of axo-glial units, including the paranodal length[22], we examined the ratio of paranodal length to axon diameter, and found that it was increased in all three central nervous system (CNS) white matter regions of ngr1−/− compared to ngr1+/+ mice (Fig. 1H and J)
As the axon diameter is intimately linked to myelin thickness[25], our findings suggest that reduced axon diameter in the CNS of ngr1−/− mice may be related to the incomplete myelination
Summary
Myelination ensures that action potentials are propagated along axons effectively. The initial contact between the central nervous system (CNS) myelin-forming oligodendrocytes and axons they ensheath, occurs at paranodal regions, which flank the node of Ranvier where voltage-gated sodium channels (Nav) are enriched[1]. Proteins enriched at paranodal regions such as contactin-1 and contactin-associated protein (Caspr), play an important role in establishing the dynamic and reciprocal relationship, from structural and functional perspectives, between the myelin extension of the mature oligodendrocyte and the axons it ensheaths, defined as the axo-glial units (for review, see refs 2, 3). The balance between plasticity and stability has been identified through the generation or loss of Nogo-A-dependent strong dendritic synapses[20] Such anatomical and physiological axo-dendritic modifications inevitably confer behavioural differences in ngr1−/− mice when compared to their wild type littermates[21]. We report ultrastructural differences of CNS axo-glial units of adult ngr1−/− compared to ngr1+/+ littermates Both axonal diameter and myelin thickness were found to be thinner in ngr1−/− mice. The data may suggest that in ngr1−/− mice there exist an altered axo-glial architecture and that this may be related to Caspr distribution that is NgR1-dependent
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