Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice
Copyright policy )Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice
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.
- Vanderbilt University United States
Male, Heterozygote, Neurosciences. Biological psychiatry. Neuropsychiatry, Epilepsies, Myoclonic, Mice, Transgenic, Nerve Tissue Proteins, In Vitro Techniques, Hippocampus, Mouse model, Membrane Potentials, Mice, Seizures, Glial Fibrillary Acidic Protein, Voltage-gated sodium channel, Animals, Cells, Cultured, Neurons, Epilepsy, Glutamate Decarboxylase, Age Factors, Electric Stimulation, Modifier genes, Electrophysiology, NAV1.1 Voltage-Gated Sodium Channel, Disease Models, Animal, Animals, Newborn, Female, RC321-571
Male, Heterozygote, Neurosciences. Biological psychiatry. Neuropsychiatry, Epilepsies, Myoclonic, Mice, Transgenic, Nerve Tissue Proteins, In Vitro Techniques, Hippocampus, Mouse model, Membrane Potentials, Mice, Seizures, Glial Fibrillary Acidic Protein, Voltage-gated sodium channel, Animals, Cells, Cultured, Neurons, Epilepsy, Glutamate Decarboxylase, Age Factors, Electric Stimulation, Modifier genes, Electrophysiology, NAV1.1 Voltage-Gated Sodium Channel, Disease Models, Animal, Animals, Newborn, Female, RC321-571
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).159 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 1% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!