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

Akshitkumar M. Mistry; Christopher H. Thompson; Alison R. Miller; Carlos G. Vanoye; Alfred L. George; Jennifer A. Kearney

doi:10.1016/j.nbd.2014.01.006

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

Akshitkumar M. Mistry, Christopher H. Thompson, Alison R. Miller, Carlos G. Vanoye, Alfred L. George, Jennifer A. Kearney

Pharmacology

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133 Scopus citations

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 (I_Na) 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. I_Na 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 I_Na density between 129.Scn1a^+/- mice and wild-type littermate controls. By contrast, I_Na 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 I_Na density between wild-type and Scn1a^+/- animals. We conclude that preserved I_Na density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a^+/- mice. Furthermore, elevated I_Na 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 language	English (US)
Pages (from-to)	1-11
Number of pages	11
Journal	Neurobiology of Disease
Volume	65
DOIs	https://doi.org/10.1016/j.nbd.2014.01.006
State	Published - May 2014

Keywords

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

ASJC Scopus subject areas

Neurology

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10.1016/j.nbd.2014.01.006

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@article{b64e1db7d6ba4f21a13d7564cd59ee06,

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.}",

note = "Funding Information: We thank Andrew Tapper, Ph.D., for providing PCR primer sequences of Gad67 gene, Clint McCollom for mouse husbandry, Jennifer Kunic for TaqMan probe and primer design, and Danny Winder for assistance with current clamp experimental design and analysis. This work was supported by National Institutes of Health grants [ NS032387 to A.L.G., NS053792 , NS063097 to J.A.K.]; and Howard Hughes Medical Institute Medical Research Fellowship to A.M.M.",

year = "2014",

month = may,

doi = "10.1016/j.nbd.2014.01.006",

language = "English (US)",

volume = "65",

pages = "1--11",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Academic Press Inc.",

}

TY - JOUR

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.

N1 - Funding Information: We thank Andrew Tapper, Ph.D., for providing PCR primer sequences of Gad67 gene, Clint McCollom for mouse husbandry, Jennifer Kunic for TaqMan probe and primer design, and Danny Winder for assistance with current clamp experimental design and analysis. This work was supported by National Institutes of Health grants [ NS032387 to A.L.G., NS053792 , NS063097 to J.A.K.]; and Howard Hughes Medical Institute Medical Research Fellowship to A.M.M.

PY - 2014/5

Y1 - 2014/5

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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U2 - 10.1016/j.nbd.2014.01.006

DO - 10.1016/j.nbd.2014.01.006

M3 - Article

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AN - SCOPUS:84893470069

SN - 0969-9961

VL - 65

SP - 1

EP - 11

JO - Neurobiology of Disease

JF - Neurobiology of Disease

ER -

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

Abstract

Keywords

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