Differential targeting and functional specialization of sodium channels in cultured cerebellar granule cells

Osorio, Nancy; Alcaraz, Gisèle; Padilla, Françoise; Couraud, François; Delmas, Patrick; Crest, Marcel

doi:10.1113/jphysiol.2005.097022

Cited by 45 publications

(51 citation statements)

References 50 publications

(64 reference statements)

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“…Consistent with previous work, ankyrin G (Ank G ) and Na v 1.6 were strongly coexpressed at the AIS in 14 DIV WT CGNs (Fig. 4A) (31,35). In contrast, the proportion of Ank G -positive AIS expressing Na v 1.6 was reduced in Scn1b null CGNs (P < 0.001; Fig.…”

Section: Resultssupporting

confidence: 80%

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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.

119

159

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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...

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Section: Resultssupporting

confidence: 80%

“…This may hinder the ability to detect any alteration in axonal VGSC expression in Scn1b null CGNs in vivo (30,31). As in dissociated CGNs, transient I Na was unchanged in 14 DIV Scn1b null CGNs (Table S4).…”

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.

119

159

View full text Add to dashboard Cite

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“…Under current-clamp conditions, CGCs of 7-11 days in vitro showed negative resting potential (À63 AE 2 mV, n ¼ 5), and spontaneous synaptic inputs in the form of bursting patterns as previously described [Becherer et al, 1997;Osorio et al, 2005], usually observed once or twice over a 2 min recording interval. Bath application of 10 mM gambierol did not affect the resting membrane potential of CGCs; however, it caused small oscillation of the membrane potential and repetitive firing (Fig.…”

Section: Effect Of Gambierol On Sodium and Potassium Currents In Cerementioning

confidence: 91%

“…For voltage-dependent sodium channels voltage-gated ion currents were elicited in CGCs by applying a series of 25 ms depolarizing pulses (voltage steps), in 5 mV increments, from a holding potential of À100 mV [Osorio et al, 2005]. Current-voltage (I-V) relationship for transient, voltage-gated sodium currents were obtained by measuring the peak amplitude of the current for each given membrane potential during the voltage steps.…”

Section: Electrophysiologymentioning

confidence: 99%

Calcium oscillations induced by gambierol in cerebellar granule cells

Albrecht¹,

Vale²,

Sasaki³

et al. 2010

J of Cellular Biochemistry

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Gambierol is a marine polyether ladder toxin derived from the dinoflagellate Gambierdiscus toxicus. To date, gambierol has been reported to act either as a partial agonist or as an antagonist of sodium channels or as a blocker of voltage-dependent potassium channels. In this work, we examined the cellular effect of gambierol on cytosolic calcium concentration, membrane potential and sodium and potassium membrane currents in primary cultures of cerebellar granule cells. We found that at concentrations ranging from 0.1 to 30 microM, gambierol-evoked [Ca(2+)]c oscillations that were dependent on the presence of extracellular calcium, irreversible and highly synchronous. Gambierol-evoked [Ca(2+)]c oscillations were completely eliminated by the NMDA receptor antagonist APV and by riluzole and delayed by CNQX. In addition, the K(+) channel blocker 4-aminopyridine (4-AP)-evoked cytosolic calcium oscillations in this neuronal system that were blocked by APV and delayed in the presence of CNQX. Electrophysiological recordings indicated that gambierol caused membrane potential oscillations, decreased inward sodium current amplitude and decreased also outward IA and IK current amplitude. The results presented here point to a common mechanism of action for gambierol and 4-AP and indicate that gambierol-induced oscillations in cerebellar neurons are most likely secondary to a blocking action of the toxin on voltage-dependent potassium channels and hyperpolarization of sodium current activation.

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“…In vitro studies have demonstrated that the Na v 1.2 subunit encoded by Scn2a localizes to the axon initial segment in cerebellar granule cells [267] and that pharmacological modulation of voltage-gated sodium channel activity in cortical neurons influences neurite length and complexity as well as density of spines and excitatory synapses [123, 124]. Alternative splicing of Scn2a results in differential expression of the various isoforms during development and adulthood [121], possibly as a means of controlling neuronal excitation.…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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Differential targeting and functional specialization of sodium channels in cultured cerebellar granule cells

Cited by 45 publications

References 50 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

Calcium oscillations induced by gambierol in cerebellar granule cells

Autism spectrum disorder: neuropathology and animal models

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Differential targeting and functional specialization of sodium channels in cultured cerebellar granule cells

Cited by 45 publications

References 50 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

Calcium oscillations induced by gambierol in cerebellar granule cells

Autism spectrum disorder: neuropathology and animal models

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