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

• Published in: Neurobiology of disease Vol. 65; pp. 1 - 11
• Main Authors: Mistry, Akshitkumar M, Thompson, Christopher H, Miller, Alison R, Vanoye, Carlos G, George,, Alfred L, Kearney, Jennifer A
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2014; Elsevier
• Subjects: Age Factors; Animals; Animals, Newborn; Cells, Cultured; Disease Models, Animal; Electric Stimulation; Electrophysiology; Epilepsies, Myoclonic - genetics; Epilepsies, Myoclonic - pathology; Epilepsies, Myoclonic - physiopathology; Epilepsy; 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; Modifier genes; Mouse model; NAV1.1 Voltage-Gated Sodium Channel - deficiency; NAV1.1 Voltage-Gated Sodium Channel - physiology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Neurons - drug effects; Neurons - physiology; Seizures; Voltage-gated sodium channel; Electrophysiology; Mouse model; Modifier genes; Epilepsy; Seizures; Voltage-gated sodium channel
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2014.01.006

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.