Effects in neocortical neurons of mutations of the Nav1.2 Na+ channel causing benign familial neonatal-infantile seizures

Paolo Scalmani, Raffaella Rusconi, Elena Armatura, Federico Zara, Giuliano Avanzini, Silvana Franceschetti, Massimo Mantegazza

Research output: Contribution to journalArticle

Abstract

Mutations of voltage-gated Na+ 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 v1.2 Na+ 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+ 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+ 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+ currents, consistently with hyperexcitability. Thus, the pathogenic mechanism of BFNIS mutations is neuronal hyperexcitability caused by increased Na+ current.

Original languageEnglish
Pages (from-to)10100-10109
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number40
DOIs
Publication statusPublished - Oct 4 2006

Fingerprint

Benign Neonatal Epilepsy
Neurons
Mutation

Keywords

  • Cortex
  • Current
  • Epilepsy
  • Excitability
  • Neonatal
  • Seizures
  • Sodium channel

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Effects in neocortical neurons of mutations of the Nav1.2 Na+ channel causing benign familial neonatal-infantile seizures. / Scalmani, Paolo; Rusconi, Raffaella; Armatura, Elena; Zara, Federico; Avanzini, Giuliano; Franceschetti, Silvana; Mantegazza, Massimo.

In: Journal of Neuroscience, Vol. 26, No. 40, 04.10.2006, p. 10100-10109.

Research output: Contribution to journalArticle

Scalmani, Paolo ; Rusconi, Raffaella ; Armatura, Elena ; Zara, Federico ; Avanzini, Giuliano ; Franceschetti, Silvana ; Mantegazza, Massimo. / Effects in neocortical neurons of mutations of the Nav1.2 Na+ channel causing benign familial neonatal-infantile seizures. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 40. pp. 10100-10109.
@article{44d09d16b0b34067905455a758525d93,
title = "Effects in neocortical neurons of mutations of the Nav1.2 Na+ channel causing benign familial neonatal-infantile seizures",
abstract = "Mutations of voltage-gated Na+ 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 v1.2 Na+ 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+ 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+ 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+ currents, consistently with hyperexcitability. Thus, the pathogenic mechanism of BFNIS mutations is neuronal hyperexcitability caused by increased Na+ current.",
keywords = "Cortex, Current, Epilepsy, Excitability, Neonatal, Seizures, Sodium channel",
author = "Paolo Scalmani and Raffaella Rusconi and Elena Armatura and Federico Zara and Giuliano Avanzini and Silvana Franceschetti and Massimo Mantegazza",
year = "2006",
month = "10",
day = "4",
doi = "10.1523/JNEUROSCI.2476-06.2006",
language = "English",
volume = "26",
pages = "10100--10109",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "40",

}

TY - JOUR

T1 - Effects in neocortical neurons of mutations of the Nav1.2 Na+ channel causing benign familial neonatal-infantile seizures

AU - Scalmani, Paolo

AU - Rusconi, Raffaella

AU - Armatura, Elena

AU - Zara, Federico

AU - Avanzini, Giuliano

AU - Franceschetti, Silvana

AU - Mantegazza, Massimo

PY - 2006/10/4

Y1 - 2006/10/4

N2 - Mutations of voltage-gated Na+ 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 v1.2 Na+ 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+ 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+ 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+ currents, consistently with hyperexcitability. Thus, the pathogenic mechanism of BFNIS mutations is neuronal hyperexcitability caused by increased Na+ current.

AB - Mutations of voltage-gated Na+ 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 v1.2 Na+ 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+ 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+ 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+ currents, consistently with hyperexcitability. Thus, the pathogenic mechanism of BFNIS mutations is neuronal hyperexcitability caused by increased Na+ current.

KW - Cortex

KW - Current

KW - Epilepsy

KW - Excitability

KW - Neonatal

KW - Seizures

KW - Sodium channel

UR - http://www.scopus.com/inward/record.url?scp=33749515473&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749515473&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2476-06.2006

DO - 10.1523/JNEUROSCI.2476-06.2006

M3 - Article

C2 - 17021166

AN - SCOPUS:33749515473

VL - 26

SP - 10100

EP - 10109

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 40

ER -