Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype

Amanda L. Blasius, Adrienne E. Dubin, Matt J. Petrus, Byung Kwan Lim, Anna Narezkina, José R. Criado, Derek N. Wills, Yu Xia, Eva Marie Y Moresco, Cindy Ehlers, Kirk U. Knowlton, Ardem Patapoutian, Bruce Beutler

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The voltage-gated sodium channel Na v1.8 is known to function in the transmission of pain signals induced by cold, heat, and mechanical stimuli. Sequence variants of human Nav1.8 have been linked to altered cardiac conduction. We identified an allele of Scn10a encoding the α-subunit of Na v1.8 among mice homozygous for N-ethyl-N-nitrosourea-induced mutations. The allele creates a dominant neurobehavioral phenotype termed Possum, characterized by transient whole-body tonic immobility induced by pinching the skin at the back of the neck ("scruffing"). The Possum mutation enhanced Na v1.8 sodium currents and neuronal excitability and heightened sensitivity of mutants to cold stimuli. Striking electroencephalographic changes were observed concomitant with the scruffing-induced behavioral change. In addition, electrocardiography demonstrated that Possummice exhibited marked sinus bradycardia and R-R variability upon scruffing, abrogated by infusion of atropine. However, atropine failed to prevent or mitigate the tonic immobility response. Hyperactive sodium conduction via Na v1.8 thus leads to a complex neurobehavioral phenotype, which resembles catatonia in schizophrenic humans and tonic immobility in other mammals upon application of a discrete stimulus; no other form of mechano-sensory stimulus could induce the immobility phenotype. Our data confirm the involvement of Na v1.8 in transducing pain initiated by cold and additionally implicate Na v1.8 in previously unknown functions in the central nervous system and heart.

Original languageEnglish (US)
Pages (from-to)19413-19418
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number48
DOIs
StatePublished - Nov 29 2011

Fingerprint

Voltage-Gated Sodium Channels
Phenotype
Atropine
Mutation
Tonic Immobility Response
Sodium
Alleles
Catatonia
Ethylnitrosourea
Genes
Pain
Bradycardia
Mammals
Electrocardiography
Neck
Central Nervous System
Hot Temperature
Skin

Keywords

  • Cold sensitivity
  • EEG
  • Scruffing

ASJC Scopus subject areas

  • General

Cite this

Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype. / Blasius, Amanda L.; Dubin, Adrienne E.; Petrus, Matt J.; Lim, Byung Kwan; Narezkina, Anna; Criado, José R.; Wills, Derek N.; Xia, Yu; Moresco, Eva Marie Y; Ehlers, Cindy; Knowlton, Kirk U.; Patapoutian, Ardem; Beutler, Bruce.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 48, 29.11.2011, p. 19413-19418.

Research output: Contribution to journalArticle

Blasius, AL, Dubin, AE, Petrus, MJ, Lim, BK, Narezkina, A, Criado, JR, Wills, DN, Xia, Y, Moresco, EMY, Ehlers, C, Knowlton, KU, Patapoutian, A & Beutler, B 2011, 'Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 48, pp. 19413-19418. https://doi.org/10.1073/pnas.1117020108
Blasius, Amanda L. ; Dubin, Adrienne E. ; Petrus, Matt J. ; Lim, Byung Kwan ; Narezkina, Anna ; Criado, José R. ; Wills, Derek N. ; Xia, Yu ; Moresco, Eva Marie Y ; Ehlers, Cindy ; Knowlton, Kirk U. ; Patapoutian, Ardem ; Beutler, Bruce. / Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 48. pp. 19413-19418.
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AU - Lim, Byung Kwan

AU - Narezkina, Anna

AU - Criado, José R.

AU - Wills, Derek N.

AU - Xia, Yu

AU - Moresco, Eva Marie Y

AU - Ehlers, Cindy

AU - Knowlton, Kirk U.

AU - Patapoutian, Ardem

AU - Beutler, Bruce

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N2 - The voltage-gated sodium channel Na v1.8 is known to function in the transmission of pain signals induced by cold, heat, and mechanical stimuli. Sequence variants of human Nav1.8 have been linked to altered cardiac conduction. We identified an allele of Scn10a encoding the α-subunit of Na v1.8 among mice homozygous for N-ethyl-N-nitrosourea-induced mutations. The allele creates a dominant neurobehavioral phenotype termed Possum, characterized by transient whole-body tonic immobility induced by pinching the skin at the back of the neck ("scruffing"). The Possum mutation enhanced Na v1.8 sodium currents and neuronal excitability and heightened sensitivity of mutants to cold stimuli. Striking electroencephalographic changes were observed concomitant with the scruffing-induced behavioral change. In addition, electrocardiography demonstrated that Possummice exhibited marked sinus bradycardia and R-R variability upon scruffing, abrogated by infusion of atropine. However, atropine failed to prevent or mitigate the tonic immobility response. Hyperactive sodium conduction via Na v1.8 thus leads to a complex neurobehavioral phenotype, which resembles catatonia in schizophrenic humans and tonic immobility in other mammals upon application of a discrete stimulus; no other form of mechano-sensory stimulus could induce the immobility phenotype. Our data confirm the involvement of Na v1.8 in transducing pain initiated by cold and additionally implicate Na v1.8 in previously unknown functions in the central nervous system and heart.

AB - The voltage-gated sodium channel Na v1.8 is known to function in the transmission of pain signals induced by cold, heat, and mechanical stimuli. Sequence variants of human Nav1.8 have been linked to altered cardiac conduction. We identified an allele of Scn10a encoding the α-subunit of Na v1.8 among mice homozygous for N-ethyl-N-nitrosourea-induced mutations. The allele creates a dominant neurobehavioral phenotype termed Possum, characterized by transient whole-body tonic immobility induced by pinching the skin at the back of the neck ("scruffing"). The Possum mutation enhanced Na v1.8 sodium currents and neuronal excitability and heightened sensitivity of mutants to cold stimuli. Striking electroencephalographic changes were observed concomitant with the scruffing-induced behavioral change. In addition, electrocardiography demonstrated that Possummice exhibited marked sinus bradycardia and R-R variability upon scruffing, abrogated by infusion of atropine. However, atropine failed to prevent or mitigate the tonic immobility response. Hyperactive sodium conduction via Na v1.8 thus leads to a complex neurobehavioral phenotype, which resembles catatonia in schizophrenic humans and tonic immobility in other mammals upon application of a discrete stimulus; no other form of mechano-sensory stimulus could induce the immobility phenotype. Our data confirm the involvement of Na v1.8 in transducing pain initiated by cold and additionally implicate Na v1.8 in previously unknown functions in the central nervous system and heart.

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