Altered Subthreshold Sodium Currents and Disrupted Firing Patterns in Purkinje Neurons of Scn8a Mutant Mice

Raman, Indira M.; Sprunger, Leslie K.; Meisler, Miriam H.; Bean, Bruce P.

doi:10.1016/s0896-6273(00)80969-1

Cited by 368 publications

(396 citation statements)

References 39 publications

Supporting

Mentioning

360

Contrasting

Order By: Relevance

“…VGSC complexes along the neurite are proposed to participate in cell-cell adhesion and fasciculation (22). (B) In 14 DIV CGNs, β1 is also required for Na v 1.6 expression at the AIS, and subsequent high-frequency AP firing through modulation of resurgent INa (8,10,45). Electrical activity may further promote β1-mediated neurite outgrowth at or near the growth cone in vivo (8,10,45).…”

Section: Resultsmentioning

confidence: 99%

“…(B) In 14 DIV CGNs, β1 is also required for Na v 1.6 expression at the AIS, and subsequent high-frequency AP firing through modulation of resurgent INa (8,10,45). Electrical activity may further promote β1-mediated neurite outgrowth at or near the growth cone in vivo (8,10,45). Thus, the developmental functions of β1 and Na v 1.6 are complementary, such that Na + influx carried by Na v 1.6 is required for β1-mediated neurite outgrowth and β1 is required for normal expression/activity of Na v 1.6 at the AIS.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Brackenbury

Chen

Miyazaki

et al. 2010

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

122

159

View full text Add to dashboard Cite

Voltage-gated Na + channel (VGSC) β1 subunits regulate cell-cell adhesion and channel activity in vitro. We previously showed that β1 promotes neurite outgrowth in cerebellar granule neurons (CGNs) via homophilic cell adhesion, fyn kinase, and contactin. Here we demonstrate that β1-mediated neurite outgrowth requires Na + current (I Na ) mediated by Na v 1.6. In addition, β1 is required for highfrequency action potential firing. Transient I Na is unchanged in Scn1b (β1) null CGNs; however, the resurgent I Na , thought to underlie high-frequency firing in Na v 1.6-expressing cerebellar neurons, is reduced. The proportion of axon initial segments (AIS) expressing Na v 1.6 is reduced in Scn1b null cerebellar neurons. In place of Na v 1.6 at the AIS, we observed an increase in Na v 1.1, whereas Na v 1.2 was unchanged. This indicates that β1 is required for normal localization of Na v 1.6 at the AIS during the postnatal developmental switch to Na v 1.6-mediated high-frequency firing. In agreement with this, β1 is normally expressed with α subunits at the AIS of P14 CGNs. We propose reciprocity of function between β1 and Na v 1.6 such that β1-mediated neurite outgrowth requires Na v 1.6-mediated I Na , and Na v 1.6 localization and consequent high-frequency firing require β1. We conclude that VGSC subunits function in macromolecular signaling complexes regulating both neuronal excitability and migration during cerebellar development.V oltage-gated Na + channels (VGSCs), composed of one poreforming α subunit and two β subunits (1), are responsible for initiation and conduction of action potentials (APs) (2). Of the nine α subunits (3), Na v 1.1, Na v 1.2, and Na v 1.6 are found in the postnatal CNS (4, 5) where they display developmentally regulated expression patterns in specialized neuronal subcellular domains. For example, Na v 1.1 and Na v 1.2 are replaced during postnatal development at the axon initial segment (AIS) and nodes of Ranvier by Na v 1.6. Scn8a null mice display motor dysfunction, ataxia, and lethality by postnatal day (P) 21, suggesting that this developmental switch to Na v 1.6 expression in brain is critical (6, 7). Scn8a null retinal ganglion neurons display impaired excitability, demonstrating that Na v 1.6 is vital for high-frequency firing (8-10). Thus, VGSC-driven neuronal activity is important for proper CNS development, although the underlying mechanism(s) are not well understood.VGSC β1 subunits are multifunctional molecules that modulate channel kinetics and gating, regulate channel cell surface expression, and participate in cell-cell adhesion in vitro (11). Scn1b (β1) null mice are ataxic, experience spontaneous seizures, and exhibit a prolonged cardiac QT interval, demonstrating that β1 modulates electrical excitability in vivo (12, 13). Consistent with this, human mutations in SCN1B result in epilepsy and arrhythmia (14-21). As a member of the Ig superfamily of cell adhesion molecules (CAMs), β1 mediates cellular aggregation, cytoskeletal recruitment, and extracellular matrix interactio...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Brackenbury

Chen

Miyazaki

et al. 2010

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

122

159

View full text Add to dashboard Cite

show abstract

“…For example, a 10 mV shift in the voltage dependence of activation of mouse SCN8A alters the repetitive firing pattern of cerebellar Purkinje neurons and produces ataxia. 30,31 A small increase in persistent current in SCN2A produces a seizure disorder in transgenic mice. 21 SCN1A mutations responsible for GEFS þ cause only minor changes in channel kinetics.…”

Section: Discussionmentioning

confidence: 99%

Sodium channels SCN1A, SCN2A and SCN3A in familial autism

et al. 2003

View full text Add to dashboard Cite

Autism is a psychiatric disorder with estimated heritability of 90%. One-third of autistic individuals experience seizures. A susceptibility locus for autism was mapped near a cluster of voltage-gated sodium channel genes on chromosome 2. Mutations in two of these genes, SCN1A and SCN2A, result in the seizure disorder GEFS þ . To evaluate these sodium channel genes as candidates for the autism susceptibility locus, we screened for variation in coding exons and splice sites in 117 multiplex autism families. A total of 27 kb of coding sequence and 3 kb of intron sequence were screened. Only six families carried variants with potential effects on sodium channel function. Five coding variants and one lariat branchpoint mutation were each observed in a single family, but were not present in controls. The variant R1902C in SCN2A is located in the calmodulin binding site and was found to reduce binding affinity for calcium-bound calmodulin. R542Q in SCN1A was observed in one autism family and had previously been identified in a patient with juvenile myoclonic epilepsy. The effect of the lariat branchpoint mutation was tested in cultured lymphoblasts. Additional population studies and functional tests will be required to evaluate pathogenicity of the coding and lariat site variants. SNP density was 1/kb in the genomic sequence screened. We report 38 sodium channel SNPs that will be useful in future association and linkage studies.

show abstract

“…Cerebellar Purkinje cells (PCs) are FSNs, which express both a resurgent Na + current (Raman et al, 1997) and Kv3 K + channels (Martina et al, 2003;McKay and Turner, 2004). Kv3 currents have been studied in outside-out somatic and dendritic patches pulled from PCs from rats in a late phase of development, when they express the Kv3.3 and Kv3.4 subunits (Martina et al, 2003;McKay and Turner, 2004).…”

Section: Introductionmentioning

confidence: 99%

Properties and expression of Kv3 channels in cerebellar Purkinje cells

Sacco

Luca

Tempia

2006

Molecular and Cellular Neuroscience

View full text Add to dashboard Cite

In cerebellar Purkinje cells, Kv3 potassium channels are indispensable for firing at high frequencies. In Purkinje cells from young mice (P4-P7), Kv3 currents, recorded in whole-cell in slices, activated at −30 mV, with rapid activation and deactivation kinetics, and they were partially blocked by blood depressing substance-I (BDS-I, 1 μM). At positive potentials, Kv3 currents were slowly but completely inactivating, while the recovery from inactivation was about eightfold slower, suggesting that a previous firing activity or a small change of the resting potential could in principle accumulate inactivated Kv3 channels, thereby finely tuning Kv3 current availability for subsequent action potentials. Single-cell RT-PCR analysis showed the expression by all Purkinje cells (n = 10 for each subunit) of Kv3.1, Kv3.3 and Kv3.4 mRNA, while Kv3.2 was not expressed. These results add to the framework for interpreting the physiological function and the molecular determinants of Kv3 currents in cerebellar Purkinje cells.

show abstract

Altered Subthreshold Sodium Currents and Disrupted Firing Patterns in Purkinje Neurons of Scn8a Mutant Mice

Cited by 368 publications

References 39 publications

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Sodium channels SCN1A, SCN2A and SCN3A in familial autism

Properties and expression of Kv3 channels in cerebellar Purkinje cells

Contact Info

Product

Resources

About

Altered Subthreshold Sodium Currents and Disrupted Firing Patterns in Purkinje Neurons of Scn8a Mutant Mice

Cited by 368 publications

References 39 publications

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Functional reciprocity between Na + channel Na v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Sodium channels SCN1A, SCN2A and SCN3A in familial autism

Properties and expression of Kv3 channels in cerebellar Purkinje cells

Contact Info

Product

Resources

About

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

Functional reciprocity between Na ⁺ channel Na _v 1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth