Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice

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Abstract

Heterozygous loss-of-function SCN1A mutations cause Dravet syndrome, an epileptic encephalopathy of infancy that exhibits variable clinical severity. We utilized a heterozygous Scn1a knockout (Scn1a+/-) mouse model of Dravet syndrome to investigate the basis for phenotype variability. These animals exhibit strain-dependent seizure severity and survival. Scn1a+/- mice on strain 129S6/SvEvTac (129.Scn1a+/-) have no overt phenotype and normal survival compared with Scn1a+/- mice bred to C57BL/6J (F1.Scn1a+/-) that have severe epilepsy and premature lethality. We tested the hypothesis that strain differences in sodium current (INa) density in hippocampal neurons contribute to these divergent phenotypes. Whole-cell voltage-clamp recording was performed on acutely-dissociated hippocampal neurons from postnatal days 21-24 (P21-24) 129.Scn1a+/- or F1.Scn1a+/- mice and wild-type littermates. INa density was lower in GABAergic interneurons from F1.Scn1a+/- mice compared to wild-type littermates, while on the 129 strain there was no difference in GABAergic interneuron INa density between 129.Scn1a+/- mice and wild-type littermate controls. By contrast, INa density was elevated in pyramidal neurons from both 129.Scn1a+/- and F1.Scn1a+/- mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1.Scn1a+/- neurons. We also observed age-dependent differences in pyramidal neuron INa density between wild-type and Scn1a+/- animals. We conclude that preserved INa density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a+/- mice. Furthermore, elevated INa density in excitatory pyramidal neurons at P21-24 correlates with age-dependent onset of lethality in F1.Scn1a+/- mice. Our findings illustrate differences in hippocampal neurons that may underlie strain- and age-dependent phenotype severity in a Dravet syndrome mouse model, and emphasize a contribution of pyramidal neuron excitability.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalNeurobiology of Disease
Volume65
DOIs
StatePublished - May 1 2014

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Myoclonic Epilepsy
Epilepsy
Sodium
Neurons
Pyramidal Cells
Phenotype
Interneurons
Wild Animals
Brain Diseases
Age of Onset
Knockout Mice
Action Potentials
Seizures

Keywords

  • Electrophysiology
  • Epilepsy
  • Modifier genes
  • Mouse model
  • Seizures
  • Voltage-gated sodium channel

ASJC Scopus subject areas

  • Neurology

Cite this

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title = "Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice",
abstract = "Heterozygous loss-of-function SCN1A mutations cause Dravet syndrome, an epileptic encephalopathy of infancy that exhibits variable clinical severity. We utilized a heterozygous Scn1a knockout (Scn1a+/-) mouse model of Dravet syndrome to investigate the basis for phenotype variability. These animals exhibit strain-dependent seizure severity and survival. Scn1a+/- mice on strain 129S6/SvEvTac (129.Scn1a+/-) have no overt phenotype and normal survival compared with Scn1a+/- mice bred to C57BL/6J (F1.Scn1a+/-) that have severe epilepsy and premature lethality. We tested the hypothesis that strain differences in sodium current (INa) density in hippocampal neurons contribute to these divergent phenotypes. Whole-cell voltage-clamp recording was performed on acutely-dissociated hippocampal neurons from postnatal days 21-24 (P21-24) 129.Scn1a+/- or F1.Scn1a+/- mice and wild-type littermates. INa density was lower in GABAergic interneurons from F1.Scn1a+/- mice compared to wild-type littermates, while on the 129 strain there was no difference in GABAergic interneuron INa density between 129.Scn1a+/- mice and wild-type littermate controls. By contrast, INa density was elevated in pyramidal neurons from both 129.Scn1a+/- and F1.Scn1a+/- mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1.Scn1a+/- neurons. We also observed age-dependent differences in pyramidal neuron INa density between wild-type and Scn1a+/- animals. We conclude that preserved INa density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a+/- mice. Furthermore, elevated INa density in excitatory pyramidal neurons at P21-24 correlates with age-dependent onset of lethality in F1.Scn1a+/- mice. Our findings illustrate differences in hippocampal neurons that may underlie strain- and age-dependent phenotype severity in a Dravet syndrome mouse model, and emphasize a contribution of pyramidal neuron excitability.",
keywords = "Electrophysiology, Epilepsy, Modifier genes, Mouse model, Seizures, Voltage-gated sodium channel",
author = "Mistry, {Akshitkumar M.} and Thompson, {Christopher H.} and Miller, {Alison R.} and Vanoye, {Carlos G.} and George, {Alfred L.} and Kearney, {Jennifer A.}",
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T1 - Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice

AU - Mistry, Akshitkumar M.

AU - Thompson, Christopher H.

AU - Miller, Alison R.

AU - Vanoye, Carlos G.

AU - George, Alfred L.

AU - Kearney, Jennifer A.

PY - 2014/5/1

Y1 - 2014/5/1

N2 - Heterozygous loss-of-function SCN1A mutations cause Dravet syndrome, an epileptic encephalopathy of infancy that exhibits variable clinical severity. We utilized a heterozygous Scn1a knockout (Scn1a+/-) mouse model of Dravet syndrome to investigate the basis for phenotype variability. These animals exhibit strain-dependent seizure severity and survival. Scn1a+/- mice on strain 129S6/SvEvTac (129.Scn1a+/-) have no overt phenotype and normal survival compared with Scn1a+/- mice bred to C57BL/6J (F1.Scn1a+/-) that have severe epilepsy and premature lethality. We tested the hypothesis that strain differences in sodium current (INa) density in hippocampal neurons contribute to these divergent phenotypes. Whole-cell voltage-clamp recording was performed on acutely-dissociated hippocampal neurons from postnatal days 21-24 (P21-24) 129.Scn1a+/- or F1.Scn1a+/- mice and wild-type littermates. INa density was lower in GABAergic interneurons from F1.Scn1a+/- mice compared to wild-type littermates, while on the 129 strain there was no difference in GABAergic interneuron INa density between 129.Scn1a+/- mice and wild-type littermate controls. By contrast, INa density was elevated in pyramidal neurons from both 129.Scn1a+/- and F1.Scn1a+/- mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1.Scn1a+/- neurons. We also observed age-dependent differences in pyramidal neuron INa density between wild-type and Scn1a+/- animals. We conclude that preserved INa density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a+/- mice. Furthermore, elevated INa density in excitatory pyramidal neurons at P21-24 correlates with age-dependent onset of lethality in F1.Scn1a+/- mice. Our findings illustrate differences in hippocampal neurons that may underlie strain- and age-dependent phenotype severity in a Dravet syndrome mouse model, and emphasize a contribution of pyramidal neuron excitability.

AB - Heterozygous loss-of-function SCN1A mutations cause Dravet syndrome, an epileptic encephalopathy of infancy that exhibits variable clinical severity. We utilized a heterozygous Scn1a knockout (Scn1a+/-) mouse model of Dravet syndrome to investigate the basis for phenotype variability. These animals exhibit strain-dependent seizure severity and survival. Scn1a+/- mice on strain 129S6/SvEvTac (129.Scn1a+/-) have no overt phenotype and normal survival compared with Scn1a+/- mice bred to C57BL/6J (F1.Scn1a+/-) that have severe epilepsy and premature lethality. We tested the hypothesis that strain differences in sodium current (INa) density in hippocampal neurons contribute to these divergent phenotypes. Whole-cell voltage-clamp recording was performed on acutely-dissociated hippocampal neurons from postnatal days 21-24 (P21-24) 129.Scn1a+/- or F1.Scn1a+/- mice and wild-type littermates. INa density was lower in GABAergic interneurons from F1.Scn1a+/- mice compared to wild-type littermates, while on the 129 strain there was no difference in GABAergic interneuron INa density between 129.Scn1a+/- mice and wild-type littermate controls. By contrast, INa density was elevated in pyramidal neurons from both 129.Scn1a+/- and F1.Scn1a+/- mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1.Scn1a+/- neurons. We also observed age-dependent differences in pyramidal neuron INa density between wild-type and Scn1a+/- animals. We conclude that preserved INa density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a+/- mice. Furthermore, elevated INa density in excitatory pyramidal neurons at P21-24 correlates with age-dependent onset of lethality in F1.Scn1a+/- mice. Our findings illustrate differences in hippocampal neurons that may underlie strain- and age-dependent phenotype severity in a Dravet syndrome mouse model, and emphasize a contribution of pyramidal neuron excitability.

KW - Electrophysiology

KW - Epilepsy

KW - Modifier genes

KW - Mouse model

KW - Seizures

KW - Voltage-gated sodium channel

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DO - 10.1016/j.nbd.2014.01.006

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