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The Journal of Neuroscience, August 6, 2003, 23(18):7001-7011

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Paranodal Interactions Regulate Expression of Sodium Channel Subtypes and Provide a Diffusion Barrier for the Node of Ranvier

Jose C. Rios,¹ Marina Rubin,¹ Mary St. Martin,¹ Ryan T. Downey,⁵ Steven Einheber,¹ Jack Rosenbluth,³ S. Rock Levinson,⁵ Manzoor Bhat,⁶ and James L. Salzer^1,2,4

Departments of ¹Cell Biology, ²Neurology, ³Physiology and Neuroscience and the Rusk Institute, and ⁴Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, ⁵Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262, and ⁶Cardiovascular Research Institute, Departments of Medicine and Molecular, Cell, and Developmental Biology, Mount Sinai School of Medicine, New York, New York 10029

The node of Ranvier is a distinct domain of myelinated axons that is highly enriched in sodium channels and is critical for impulse propagation. During development, the channel subtypes expressed at the node undergo a transition from Na_v1.2 to Na_v1.6. Specialized junctions that form between the paranodal glial membranes and axon flank the nodes and are candidates to regulate their maturation and delineate their boundaries. To investigate these roles, we characterized node development in mice deficient in contactin-associated protein (Caspr), an integral junctional component. Paranodes in these mice lack transverse bands, a hallmark of the mature junction, and exhibit progressive disruption of axon-paranodal loop interactions in the CNS. Caspr mutant mice display significant abnormalities at central nodes; components of the nodes progressively disperse along axons, and many nodes fail to mature properly, persistently expressing Na_v1.2 rather than Na_v1.6. In contrast, PNS nodes are only modestly longer and, although maturation is delayed, eventually all express Na_v1.6. Potassium channels are aberrantly clustered in the paranodes; these clusters are lost over time in the CNS, whereas they persist in the PNS. These findings indicate that interactions of the paranodal loops with the axon promote the transition in sodium channel subtypes at CNS nodes and provide a lateral diffusion barrier that, even in the absence of transverse bands, maintains a high concentration of components at the node and the integrity of voltage-gated channel domains.

Key words: Caspr; myelin; sodium channels; nodes; paranodal junction; potassium channels

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Received Mar. 19, 2003; revised Jun. 5, 2003; accepted Jun. 12, 2003.

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