Comparative distribution of voltage-gated sodium channel proteins in human brain

Whitaker, William R. J.; Faull, Richard L.M.; Waldvogel, Henry J.; Plumpton, Christopher; Emson, Piers C.; Clare, Jeffrey J.

doi:10.1016/s0169-328x(00)00289-8

Cited by 136 publications

(102 citation statements)

References 28 publications

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“…Although previous immunohistochemical analyses suggested that Na v 1.1 is generally localized to somata and dendrites of neurons (Westenbroek et al, 1989;Gong et al, 1999;Whitaker et al, 2001;Yu et al, 2006), our findings indicate that, with the exception of somata of hippocampal nonpyramidal cells, Na v 1.1 is generally localized to axons. Several other studies and data support this axonal Na v 1.1 localization.…”

Section: Discussioncontrasting

confidence: 95%

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Ogiwara¹,

Miyamoto²,

Morita³

et al. 2007

J. Neurosci.

783

908

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Loss-of-function mutations in human SCN1A gene encoding Na v 1.1 are associated with a severe epileptic disorder known as severe myoclonic epilepsy in infancy. Here, we generated and characterized a knock-in mouse line with a loss-of-function nonsense mutation in the Scn1a gene. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. Immunohistochemical analyses revealed that, in the developing neocortex, Na v 1.1 was clustered predominantly at the axon initial segments of parvalbumin-positive (PV) interneurons. In heterozygous knock-in mice, trains of evoked action potentials in these fast-spiking, inhibitory cells exhibited pronounced spike amplitude decrement late in the burst. Our data indicate that Na v 1.1 plays critical roles in the spike output from PV interneurons and, furthermore, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice.

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Section: Discussioncontrasting

confidence: 95%

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Ogiwara¹,

Miyamoto²,

Morita³

et al. 2007

J. Neurosci.

783

908

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“…Genetically engineered knock-in mice carrying a pathogenic FHM1 mutation revealed gain-of-function effects with increased calcium influx and neurotransmitter release resulting in a reduced CSD threshold (25), supporting the concept that the migrainous brain is hyperexcitable (26). Whereas, Ca V 2.1 channels and ␣ 2 -containing Na ϩ /K ϩ -ATPase pumps are expressed in and around glutamatergic synapses, Na V 1.1 channels are expressed somatodendritically (27)(28)(29)(30)(31) and in the axonal initial segment (32)(33)(34), where they may contribute to integrating incoming signals and controlling neuronal excitability. Therefore, the functional defects we observed for mutant Na V 1.1 channels may cause FHM3 by nonsynaptic mechanisms.…”

Section: Pathogenesis Of Fhm3mentioning

confidence: 69%

Divergent sodium channel defects in familial hemiplegic migraine

Kahlig¹,

Rhodes²,

Pusch

et al. 2008

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

105

112

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Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltagegated sodium channel Na V1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human ␤ 1 and ␤ 2 accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-Na V1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-offunction features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of Na V1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms.epilepsy ͉ SCN1A ͉ Na V 1.1 ͉ FHM3

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“…Na v 1.2 is expressed in all of the cortical areas studied (Westenbroek et al, 1989;Gong et al, 1999;Whitaker et al, 2001), but it could have higher expression in some regions, explaining the focal onset. However, posterior cortical areas can be a common region of generation of ictal and interictal EEG discharges in very young infants, for example, in severe epilepsies caused by extra-occipital brain lesions (Oka et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the two isoforms may differentially affect the excitability of excitatory and inhibitory neurons. In the cerebral cortex and in the hippocampus, Na v 1.2 is mainly localized in axons and nerve terminals and may be particularly highly expressed in excitatory pyramidal neurons, as suggested by the dense staining of excitatory fibers (Westenbroek et al, 1989;Gong et al, 1999;Whitaker et al, 2001) and by the selective clustering at nodes of Ranvier in developing myelinated fibers (Kaplan et al, 2001). Because of this distribution, the modifications of Na v 1.2 properties may preferentially affect the functions of excitatory neurons, causing network hyperexcitability.…”

Section: Discussionmentioning

confidence: 99%

Effects in Neocortical Neurons of Mutations of the Na_v1.2 Na⁺Channel causing Benign Familial Neonatal-Infantile Seizures

Scalmani¹,

Rusconi²,

Armatura³

et al. 2006

J. Neurosci.

113

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Mutations of voltage-gated Naϩ channels are the most common cause of familial epilepsy. Benign familial neonatal-infantile seizures (BFNIS) is an epileptic trait of the early infancy, and it is the only well characterized epileptic syndrome caused exclusively by mutations of Na v 1.2 Na ϩ channels, but no functional studies of BFNIS mutations have been done. The comparative study of the functional effects and the elucidation of the pathogenic mechanisms of epileptogenic mutations is essential for designing targeted and effective therapies. However, the functional properties of Na ϩ channels and the effects of their mutations are very sensitive to the cell background and thus to the expression system used. We investigated the functional effects of four of the six BFNIS mutations identified (L1330F, L1563V, R223Q, and R1319Q) using as expression system transfected pyramidal and bipolar neocortical neurons in short primary cultures, which have small endogenous Na ϩ current and thus permit the selective study of transfected channels. The mutation L1330F caused a positive shift of the inactivation curve, and the mutation L1563V caused a negative shift of the activation curve, effects that are consistent with neuronal hyperexcitability. The mutations R223Q and R1319Q mainly caused positive shifts of both activation and inactivation curves, effects that cannot be directly associated with a specific modification of excitability. Using physiological stimuli in voltage-clamp experiments, we showed that these mutations increase both subthreshold and action Na ϩ currents, consistently with hyperexcitability. Thus, the pathogenic mechanism of BFNIS mutations is neuronal hyperexcitability caused by increased Na ϩ current.

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Comparative distribution of voltage-gated sodium channel proteins in human brain

Cited by 136 publications

References 28 publications

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Divergent sodium channel defects in familial hemiplegic migraine

Effects in Neocortical Neurons of Mutations of the Na_v1.2 Na⁺Channel causing Benign Familial Neonatal-Infantile Seizures

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Comparative distribution of voltage-gated sodium channel proteins in human brain

Cited by 136 publications

References 28 publications

Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Divergent sodium channel defects in familial hemiplegic migraine

Effects in Neocortical Neurons of Mutations of the Nav1.2 Na+Channel causing Benign Familial Neonatal-Infantile Seizures

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Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Na_v1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying anScn1aGene Mutation

Effects in Neocortical Neurons of Mutations of the Na_v1.2 Na⁺Channel causing Benign Familial Neonatal-Infantile Seizures