Behavioral phenotyping of young Scn1a haploinsufficient mice

Abstract

Dravet syndrome is a rare, severe, infancy-onset epileptic encephalopathy associated with a high premature mortality. In most patients, Dravet syndrome is caused by a heterozygous loss-of-function mutation in the SCN1A gene encoding the alpha 1 subunit of the sodium channel. Of the variety of SCN1A variants identified in patients with Dravet syndrome, SCN1A missense mutations occur in one-third of cases. The novel Scn1a-A1783V mouse model of Dravet syndrome carries the human Ala1783Val missense variant. Recently, the behavioral phenotype of Scn1a-A1783V haploinsufficient adult mice has been characterized, which may provide a valuable basis for assessment of novel therapeutic approaches. However, there is still limited information on the developmental course of behavioral alterations in the Scn1a-A1783V mouse model, which is of particular relevance for conclusions about face validity and severity classification of the model. Based on reference data from young wildtype mice, we analyzed selected behavioral parameters and fecal corticosterone metabolites in the Scn1a-A1783V mouse model during post-weaning development. Differences in the preference for a sweet saccharin solution between Dravet mice and wildtype mice were observed once mice reached sexual maturity. Nest building behavior was already influenced by the Scn1a genotype during prepubescence. Sexually mature Dravet mice showed a significantly reduced burrowing performance as compared to their wildtype littermates. In the open-field test, pronounced hyperactivity and increased thigmotactic behavior were evident in prepubescent and sexually mature Dravet mice. Analysis of Irwin scores revealed several genotype-dependent changes in handling-associated parameters during the course of adolescence. The information obtained provides insight into the age-dependence of behavioral patterns in the novel Scn1a-A1783V mouse model of Dravet syndrome. In addition, the dataset confirms the suitability of the applied behavioral composite measure scheme for evidence-based assessment of cumulative severity in genetic mouse lines.

Keywords: 3R; Adolescence; Dravet syndrome; Epilepsy; Genetic mouse model; Severity assessment.