Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6)

Kearney, Jennifer A.; Buchner, David A.; Haan, Georgius de; Adamska, Maja; Levin, Stephen I.; Furay, Amy R.; Albin, Roger L.; Jones, Julie Miller; Montal, Mauricio; Stevens, Martin J.; Sprunger, Leslie K.; Meisler, Miriam H.

doi:10.1093/hmg/11.22.2765

Cited by 91 publications

(96 citation statements)

References 30 publications

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“…Impairment in Na v channel expression results in delayed maturation of the nodes of Ranvier and slows down nerve conduction velocity (39,40), whereas mutations in nodal potassium channels are associated with myokymia, epilepsies, and encephalopathies (41,42). The mechanisms leading to the accumulation of Na v channels at the nodes in the PNS are dependent on neurofascin-186 and NrCAM (15).…”

Section: Discussionmentioning

confidence: 99%

Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy

D’Este

Kamin

Balzarotti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

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We used stimulated emission depletion (STED) superresolution microscopy to analyze the nanoscale organization of 12 glial and axonal proteins at the nodes of Ranvier of teased sciatic nerve fibers. Cytoskeletal proteins of the axon (betaIV spectrin, ankyrin G) exhibit a high degree of one-dimensional longitudinal order at nodal gaps. In contrast, axonal and glial nodal adhesion molecules [neurofascin-186, neuron glial-related cell adhesion molecule (NrCAM)] can arrange in a more complex, 2D hexagonal-like lattice but still feature a ∼190-nm periodicity. Such a lattice-like organization is also found for glial actin. Sodium and potassium channels exhibit a one-dimensional periodicity, with the Na v channels appearing to have a lower degree of organization. At paranodes, both axonal proteins (betaII spectrin, Caspr) and glial proteins (neurofascin-155, ankyrin B) form periodic quasi-one-dimensional arrangements, with a high degree of interdependence between the position of the axonal and the glial proteins. The results indicate the presence of mechanisms that finely align the cytoskeleton of the axon with the one of the Schwann cells, both at paranodal junctions (with myelin loops) and at nodal gaps (with microvilli). Taken together, our observations reveal the importance of the lateral organization of proteins at the nodes of Ranvier and pave the way for deeper investigations of the molecular ultrastructural mechanisms involved in action potential propagation, the formation of the nodes, axon-glia interactions, and demyelination diseases.nodes of Ranvier | STED nanoscopy | cytoskeleton | axon-glia interaction | sciatic nerve I n recent years, knowledge of the ultrastructural organization of the axon initial segment (AIS) has been greatly extended by using optical nanoscopy to visualize its molecular composition. Stochastic optical reconstruction microscopy (STORM) and stimulated emission depletion (STED) microscopy were indeed crucial for the identification of a ∼190-nm periodic organization of the key components of the AIS. In particular, a periodic spatial arrangement was discovered for cytoskeletal proteins (actin, ankyrin G, betaIV spectrin), adhesion molecules (neurofascin), and channels (voltage-gated sodium Na v channels) (1-4). In the distal part of the axon, this periodicity has been found for actin, adducin, ankyrin B, and betaII spectrin in virtually every neuron type from the central and peripheral nervous systems (CNS and PNS) (1, 2, 5, 6). Although myelination of axons does not alter the patterning of the subcortical cytoskeleton (5, 6), it changes its molecular composition, promoting the clustering of specific markers at the nodes of Ranvier, where the action potential is regenerated (reviewed in refs. 7, 8). At nodes of Ranvier, the myelin sheath formed by oligodendrocytes (in the CNS) or Schwann cells (in the PNS) is interrupted. Still, the nodal gap is surrounded by perinodal astrocytes and microvilli stemming from the Schwann cells in the CNS and PNS, respectively (9). Interestingly, the AIS an...

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Section: Discussionmentioning

confidence: 99%

Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy

D’Este

Kamin

Balzarotti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

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“…During normal optic nerve development, Na v 1.2 channels remain at nodes of Ranvier until Na v 1.6 channels appear (Boiko et al, 2001), and, in the medJ Na v 1.6-hypomorph, Na v 1.2 retention at nodes is prolonged until enough Na v 1.6 channels are synthesized (Kearney et al, 2002). Thus, it is perhaps not surprising that Na v 1.2 channels are retained at nodes and initial segments of med Tg animals.…”

Section: Channel Compensation In Retinal Ganglion Cells and Other Cnsmentioning

confidence: 99%

Impaired Firing and Cell-Specific Compensation in Neurons Lacking Na_v1.6 Sodium Channels

2006

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The ability of neurons to fire precise patterns of action potentials is critical for encoding inputs and efficiently driving target neurons. At the axon initial segment and nodes of Ranvier, where nerve impulses are generated and propagated, a high density of Na v 1.2 sodium channels is developmentally replaced by Na v 1.6 channels. In retinal ganglion cells (GCs), this isoform switch coincides with the developmental transition from single spikes to repetitive firing. Also, Na v 1.6 channels are required for repetitive spiking in cerebellar Purkinje neurons. These previous observations suggest that the developmental appearance of Na v 1.6 underlies the transition to repetitive spiking in GCs. To test this possibility, we recorded from GCs of med (Na v 1.6-null) and wild-type mice during postnatal development. By postnatal day 18, when the switch to Na v 1.6 at GC initial segments is normally complete, the maximal sustained and instantaneous firing rates were lower in med than in wild-type GCs, demonstrating that Na v 1.6 channels are necessary to attain physiologically relevant firing frequencies in GCs. However, the firing impairment was milder than that reported previously in med Purkinje neurons, which prompted us to look for differences in compensatory sodium channel expression. Both Na v 1.2 and Na v 1.1 channels accumulated at initial segments and nodes of med GCs, sites normally occupied by Na v 1.6. In med Purkinje cells, only Na v 1.1 channels were found at initial segments, whereas in other brain regions, only Na v 1.2 was detected at med initial segments and nodes. Thus, compensatory mechanisms in channel isoform distribution are cell specific, which likely results in different firing properties.

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“…Thermosequenase (Stratagene) was used for the extension reactions from primer 3 (5′TGC CAG AGA CAC TAA ACC GAC AGT C) in the presence of dATP, dCTP, dCTP and α 33 P-ddGTP. The relative amount of 31 bp product from the C3H allele and 33 bp product from the SJL allele was determined by densitometry using the BioRad Molecular Imager FX with Quantity One software, as described previously (Kearney et al, 2002;Buchner et al, 2003).…”

Section: Primer Extension/chain Termination Assaymentioning

confidence: 99%

Hypomorphic expression ofDkk1in thedoubleridgemouse: dose dependence and compensatory interactions withLrp6

2004

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doubleridge is a transgene-induced mouse mutation displaying forelimb postaxial polysyndactyly. We have cloned the doubleridge transgene insertion site and demonstrate that doubleridge acts in cis from a distance of 150 kb to reduce the expression of dickkopf 1 (Dkk1), the secreted Wnt antagonist. Expression of Dkk1 from the doubleridge allele ranges from 35% of wild-type level in E7.0 head to <1% of wild type in E13.5 tail.

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Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6)

Cited by 91 publications

References 30 publications

Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy

Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy

Impaired Firing and Cell-Specific Compensation in Neurons Lacking Na_v1.6 Sodium Channels

Hypomorphic expression ofDkk1in thedoubleridgemouse: dose dependence and compensatory interactions withLrp6

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Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Nav1.6)

Cited by 91 publications

References 30 publications

Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy

Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy

Impaired Firing and Cell-Specific Compensation in Neurons Lacking Nav1.6 Sodium Channels

Hypomorphic expression ofDkk1in thedoubleridgemouse: dose dependence and compensatory interactions withLrp6

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Impaired Firing and Cell-Specific Compensation in Neurons Lacking Na_v1.6 Sodium Channels