Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1

Abstract

In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily. Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location. Furthermore, we show that the localization of Caspr2 and clustering of K+ channels at the juxtaparanodal region depends on the presence of TAG-1, an immunoglobulin-like cell adhesion molecule that binds Caspr2. These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon–glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane.

Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development

“…24 and 25). Knockout of CASPR2 in mice results in epilepsy and behavioral abnormalities that are consistent with the symptoms observed in some cases of ASDs (26,27). The loss of CASPR2 in neurons, however, not only depletes K + channels from myelinated juxtaparanodal regions (26, 27) but also causes a 20% reduction in the number of interneurons in cortex, hippocampus, and striatum, as well as discrete alterations in neuronal migration and cortical layer patterning (26).…”

“…S1 G-J). Because CASPR2 is known to organize voltage-gated ion channels in axonal membrane subdomains in mature neurons (19,27,(34)(35)(36)(37), we asked whether the CASPR2 KD may produce the observed changes in synaptic transmission indirectly by altering the membrane properties of neurons. However, multiple indicators of neuronal excitability, including resting potential, action potential threshold, and spiking frequency in response to fixed current injections, were not affected by the CASPR2 KD, suggesting that the phenotype does not reflect a change in membrane properties (Fig.…”

Shining a light on CNTNAP2: complex functions to complex disorders

“…63,64 Formation of this complex is mediated by Protein 4.1B binding to the intracellular portion of CASPR2 and is required for the clustering of voltage-gated potassium channels at juxtaparanodes. 65 These channels are involved in the rapid, saltatory conduction of nerve impulses, 66 and individuals from the CDFE cohort (with homozygous CNTNAP2 mutations) display reduced potassium channel (K v 1.1) localisation in hippocampal axons. 14 However, in Cntnap2-knockout mice, no difference in nerve conduction was observed in the peripheral nervous system.…”

“…14 However, in Cntnap2-knockout mice, no difference in nerve conduction was observed in the peripheral nervous system. 65,67 CASPR2 and neuronal migration Given that CNTNAP2 expression is high at timepoints prior to the development of neuronal myelination, additional non-juxtaparanodal roles for CASPR2 have been proposed. CDFE patients carrying homozygous mutations of CNTNAP2 displayed histological abnormalities including regions of abnormal cortical thickening, poorly defined grey and white matter junctions and abnormal density and organisation of neurons.…”

Contacts cellulaires des fibres myélinisées du système nerveux périphérique

“…Il a été proposé que ces jonctions puissent également assurer une fonction de barrière, ralentissant la diffusion des molécules dans l'espace intercellulaire de la région nodale vers l'internoeud. L'étude de modèles animaux murins dont les gènes codant pour les protéines NCP et IgSF-CAM juxtaparanodales ont été invalidés -Caspr2 et TAG-1 (transiently expressed axonal glycoprotein 1), respectivement -a par ailleurs montré que ces protéines sont essentielles pour une localisation et une concentration correctes des canaux K + dans les juxtaparanoeuds [30,31]. Cette observation est intéressante sur le plan physiologique, dans la mesure où il a été proposé que les canaux K + juxtaparanodaux puissent participer au rétablissement rapide du potentiel de repos.…”