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

Neurobiol Dis. 2014 May;65:1-11. doi: 10.1016/j.nbd.2014.01.006. Epub 2014 Jan 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Disease Models, Animal
  • Electric Stimulation
  • Epilepsies, Myoclonic / genetics
  • Epilepsies, Myoclonic / pathology*
  • Epilepsies, Myoclonic / physiopathology
  • Female
  • Glial Fibrillary Acidic Protein
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Heterozygote
  • Hippocampus / pathology*
  • In Vitro Techniques
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics*
  • Mice
  • Mice, Transgenic
  • NAV1.1 Voltage-Gated Sodium Channel / deficiency
  • NAV1.1 Voltage-Gated Sodium Channel / physiology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / physiology*

Substances

  • Glial Fibrillary Acidic Protein
  • NAV1.1 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • Scn1a protein, mouse
  • glial fibrillary astrocytic protein, mouse
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1