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Propagation of action potentials along axons is optimized through interactions between neurons and myelinating glial cells. Myelination drives division of the axons into distinct molecular domains including nodes of Ranvier. The high density of voltage-gated sodium channels at nodes generates action potentials allowing for rapid and efficient saltatory nerve conduction. At paranodes flanking both sides of the nodes, myelinating glial cells interact with axons, forming junctions that are essential for node formation and maintenance. Recent studies indicate that the disruption of these specialized axonal domains is involved in the pathophysiology of various neurological diseases. Loss of paranodal axoglial junctions due to genetic mutations or autoimmune attack against the paranodal proteins leads to nerve conduction failure and neurological symptoms. Breakdown of nodal and paranodal proteins by calpains, the calcium-dependent cysteine proteases, may be a common mechanism involved in various nervous system diseases and injuries. This chapter reviews recent progress in neurobiology and pathophysiology of specialized axonal domains along myelinated nerve fibers.

The precise and remarkable subdivision of myelinated axons into molecularly and functionally distinct membrane domains depends on axoglial junctions that function as barriers. However, the molecular basis of these barriers remains poorly understood. Here, we report that genetic ablation and loss of axonal βII spectrin eradicated the paranodal barrier that normally separates juxtaparanodal K(+) channel protein complexes located beneath the myelin sheath from Na(+) channels located at nodes of Ranvier. Surprisingly, the K(+) channels and their associated proteins redistributed into paranodes where they colocalized with intact Caspr-labeled axoglial junctions. Furthermore, electron microscopic analysis of the junctions showed intact paranodal septate-like junctions. Thus, the paranodal spectrin-based submembranous cytoskeleton comprises the paranodal barriers required for myelinated axon domain organization.

In myelinated nerve fibers, action potential initiation and propagation requires that voltage-gated ion channels be clustered at high density in the axon initial segments and nodes of Ranvier. The molecular organization of these subdomains depends on specialized cytoskeletal and scaffolding proteins such as spectrins, ankyrins, and 4.1 proteins. These cytoskeletal proteins are considered to be important for 1) formation, localization, and maintenance of specific integral membrane protein complexes, 2) a barrier restricting the diffusion of both cytoplasmic and membrane proteins to distinct regions or compartments of the cell, and 3) stabilization of axonal membrane integrity. Increased insights into the role of the cytoskeleton could provide important clues about the pathophysiology of various neurological disorders.

Paranodal axo-glial junctions are important for ion channel clustering and rapid action potential propagation in myelinated nerve fibers. Paranode formation depends on the cell adhesion molecules neurofascin (NF) 155 in glia, and a Caspr and contactin heterodimer in axons. We found that antibody to ganglioside GM1 labels paranodal regions. Autoantibodies to the gangliosides GM1 and GD1a are thought to disrupt nodes of Ranvier in peripheral motor nerves and cause Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To elucidate ganglioside function at and near nodes of Ranvier, we examined nodes in mice lacking gangliosides including GM1 and GD1a. In both peripheral and central nervous systems, some paranodal loops failed to attach to the axolemma, and immunostaining of Caspr and NF155 was attenuated. K(+) channels at juxtaparanodes were mislocalized to paranodes, and nodal Na(+) channel clusters were broadened. Abnormal immunostaining at paranodes became more prominent with age. Moreover, the defects were more prevalent in ventral than dorsal roots, and less frequent in mutant mice lacking the b-series gangliosides but with excess GM1 and GD1a. Electrophysiological studies revealed nerve conduction slowing and reduced nodal Na(+) current in mutant peripheral motor nerves. The amounts of Caspr and NF155 in low density, detergent insoluble membrane fractions were reduced in mutant brains. These results indicate that gangliosides are lipid raft components that contribute to stability and maintenance of neuron-glia interactions at paranodes., ((c) 2007 Wiley-Liss, Inc.)