The fast and reliable propagation of action potentials along myelinated fibers relies on the clustering of voltage‐gated sodium channels at nodes of Ranvier. Axo‐glial communication is required for assembly of nodal proteins in the central nervous system, yet the underlying mechanisms remain poorly understood. Oligodendrocytes are known to support node of Ranvier assembly through paranodal junction formation. In addition, the formation of early nodal protein clusters (or prenodes) along axons prior to myelination has been reported, and can be induced by oligodendrocyte conditioned medium (OCM). Our recent work on cultured hippocampal neurons showed that OCM‐induced prenodes are associated with an increased conduction velocity (Freeman et al., 2015). We here unravel the nature of the oligodendroglial secreted factors. Mass spectrometry analysis of OCM identified several candidate proteins (i.e., Contactin‐1, ChL1, NrCAM, Noelin2, RPTP/Phosphacan, and Tenascin‐R). We show that Contactin‐1 combined with RPTP/Phosphacan or Tenascin‐R induces clusters of nodal proteins along hippocampal GABAergic axons. Furthermore, Contactin‐1‐immunodepleted OCM or OCM from Cntn1‐null mice display significantly reduced clustering activity, that is restored by addition of soluble Contactin‐1. Altogether, our results identify Contactin‐1 secreted by oligodendrocytes as a novel factor that may influence early steps of nodal sodium channel cluster formation along specific axon populations.

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity. In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. The mechanisms for microglia-neuron communication remain largely unkown. Here, we identify nodes of Ranvier as a direct site of interaction between microglia and axons, in both mouse and human tissues. Using dynamic imaging, we highlight the preferential interaction of microglial processes with nodes of Ranvier along myelinated fibers. We show that microglia-node interaction is modulated by neuronal activity and associated potassium release, with THIK-1 ensuring their microglial read-out. Altered axonal K+ flux following demyelination impairs the switch towards a pro-regenerative microglia phenotype and decreases remyelination rate. Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron interaction, that may participate in microglia-neuron communication mediating pro-remyelinating effect of microglia after myelin injury.

The plasticity of the central nervous system (CNS) in response to neuronal activity has been suggested as early as 1894 by Cajal (1894). CNS plasticity has first been studied with a focus on neuronal structures. However, in the last decade, myelin plasticity has been unraveled as an adaptive mechanism of importance, in addition to the previously described processes of myelin repair. Indeed, it is now clear that myelin remodeling occurs along with life and adapts to the activity of neuronal networks. Until now, it has been considered as a two-part dialog between the neuron and the oligodendroglial lineage. However, other glial cell types might be at play in myelin plasticity. In the present review, we first summarize the key structural parameters for myelination, we then describe how neuronal activity modulates myelination and finally discuss how other glial cells could participate in myelinic adaptivity.

insights and discussion, and Elisa Mazuir for technical assistance. We thank the icm.Quant imaging platform, Dr. D. Langui and D. Akbar for their support in videomicroscopy acquisitions. We thank the ICM biostatistics platform (iCONICS) for support in statistical analysis. We thank the CELIS, vectorology, genotyping and PhenoICMouse ICM facilities.

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In vertebrates, fast saltatory conduction along myelinated axons relies on the node of Ranvier. How nodes assemble on CNS neurons is not yet fully understood. We recently highlighted that clusters similar to nodes can form prior to myelin deposition in hippocampal GABAergic neurons and are associated with increased conduction velocity.Here, we used a live imaging approach to characterize the intrinsic mechanisms underlying the assembly of these early clusters. We first demonstrated that their components can partially pre-assemble prior to membrane targeting and determined the molecular motors involved in their trafficking. We then demonstrated the key role of the protein β2Nav for clustering initiation. We further unraveled the fate of these early clusters, by showing that they participate in node formation, but also have an unexpected role in guiding oligodendrocyte processes prior to myelin deposition. Altogether our results shed light on an alternative mechanism of nodal clustering and myelination onset.

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity. In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. The mechanisms for microglia-neuron communication remain largely unkown. Here, we identify nodes of Ranvier as a direct and stable site of interaction between microglia and axons, in both mouse and human tissue. Using dynamic imaging, we highlight the preferential interaction of microglial processes with nodes of Ranvier along myelinated fibers. We show that microglianode interaction is modulated by neuronal activity and associated potassium release, with THIK-1 ensuring their microglial read-out. Disrupting axonal K+ flux following demyelination polarizes microglia towards a pro-inflammatory phenotype and decreases remyelination rate. Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron communication, participating in the pro-remyelinating effect of microglia after myelin injury.

Immunochemistry (immunocytochemistry for cells and immunohistochemistry for tissues) is a method used to label specific antigens, based on highly specific antibody-epitope interactions. The resulting labeling can be visualized and imaged through microscopy adapted to the type of detection system used (fluorophore, peroxidase, etc.). In the nervous system, myelin is a complex membrane structure, generated by myelinating glial cells, which ensheath axons and facilitate electrical conduction. Myelin alteration has been shown to occur in various neurological diseases, in which it is associated with functional deficits. Here, we focus on myelin detection by immunofluorescence using immunochemistry protocols based on antibodies directed against major myelin proteins.