C57BL/6J and C57BL/6N substrains differentially influence phenotype severity in the Scn1a^+/− mouse model of Dravet syndrome

Abstract

Summary Many disease‐relevant phenotypes modeled in inbred mice have been shown to be strain‐dependent, indicating the important influence of genetic background on disease phenotypes. Although C57BL/6 mice are one of the most commonly used inbred strains in laboratory research, there are multiple substrains (eg, B6J vs B6N) that have been separated for more than 50 years. Thus, understanding the substrain differences is important for scientific rigor and reproducibility. In this study, seizure susceptibility, spontaneous seizures, and survival were compared between Scn1a+/− mice on (C57BL/6J × 129S6/SvEvTac)F1 (F1J) vs (C57BL/6N × 129S6/SvEvTac)F1 (F1N) strain backgrounds. F1N.Scn1a+/− mice were more susceptible to hyperthermia‐induced seizures, yet had milder spontaneous seizures and improved survival relative to F1J.Scn1a+/− mice. Our results indicate that choice of C57BL/6 substrain may significantly alter disease phenotypes and should be considered carefully in experimental design using the Scn1a+/− Dravet mouse model, as well as other mouse models of epilepsy.

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

“…1A). Notably, the onset of premature death and overall mortality in these Scn1a A1783V mice is very similar to that of other DS mice on the C57BL/6J genetic background (Kang et al, 2018;Ogiwara et al, 2007;Styr et al, 2019;Tsai et al, 2015;Yu et al, 2006). Moreover, as with Dravet patients, susceptibility to thermally induced seizures precedes the onset of spontaneous seizures (Dravet, 2011;Oguni et al, 2001).…”

“…Thus, in addition to modifying the survival of DS mice (Kang et al, 2018;Yu et al, 2006), genetic background also alters the febrile stage of Dravet.…”

“…Of note, susceptibility to early febrile seizures (at P14-P16) was demonstrated before (Hawkins et al, 2017 (Hawkins et al, 2017). Thus, in addition to modifying the survival of DS mice (Kang et al, 2018;Yu et al, 2006), genetic background also alters the febrile stage of Dravet.…”

New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome

“…The results of this study implied that impairing action potential generation by parvalbumin‐positive fast‐spiking basket cell interneurons contribute to the initial epilepsy phenotype but may not be the sole mechanism that drives later, chronic epilepsy in DS . It is equally important, however, to consider that the variable severity and expressivity of the murine Scn1a ± epilepsy phenotype is highly strain dependent . Therefore, it will be interesting to explore whether stabilization of interneuron activity can be recapitulated in the zebrafish scn1lab wt/mut .…”

“…47 It is equally important, however, to consider that the variable severity and expressivity of the murine Scn1a ± epilepsy phenotype is highly strain dependent. 48,49 Therefore, it will be interesting to explore whether stabilization of interneuron activity can be recapitulated in the zebrafish scn1lab wt/mut . This study describes a new zebrafish scn1a channelopathy model that recapitulates many aspects of DS and may prove useful in identifying other disease mechanisms such as the role of neuron-glia interaction and glutamatergic neurons in the process of epileptogenesis or the development of other associated comorbidities.…”