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.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA; Department of Neurosurgery, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA.
authors.forename: Akshitkumar M
authors.initials: AM
authors.lastname: Mistry
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Thompson
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA.
authors.forename: Alison R
authors.initials: AR
authors.lastname: Miller
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Vanoye
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA. Electronic address: al.george@vanderbilt.edu.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA. Electronic address: jennifer.kearney@vanderbilt.edu.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kearney
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006624:Hippocampus / Q000473:pathology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000172:deficiency / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568249:Scn1a protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1
keywords: Electrophysiology; Epilepsy; Modifier genes; Mouse model; Seizures; Voltage-gated sodium channel