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

NEUROBIOLOGY OF DISEASE

卷:65

Article

Mistry, Akshitkumar M.^1,2  Thompson, Christopher H.¹  Miller, Alison R.¹  Vanoye, Carlos G.¹  George, Alfred L., Jr.^1,3  Kearney, Jennifer A.¹ 

[1] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Sch Med, Dept Neurosurg, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA

关键词: Seizures;    Epilepsy;    Mouse model;    Voltage-gated sodium channel;    Electrophysiology;    Modifier genes;   

DOI  :  10.1016/j.nbd.2014.01.006

来源: Elsevier

【 摘 要 】

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 intemeuron 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 F1Scn1a(+/-) mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1Scn1a(+/-) 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 F1Scn1a(+/-) 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. (C) 2014 Elsevier Inc. All rights reserved.

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