Abstracts

Rationale: Severe genetic epileptic encephalopathies such as Dravet syndrome (DS) manifest in infants and young children and are characterized by frequent, difficult to control seizures. Patients with these encephalopathies may also exhibit a wide range of developmental and neurological deficits, including movement disorders.

Two primary genes, SCN1A and SCN1B, are associated with the spectrum of generalized epilepsy with febrile seizures plus (GEFS+) disorders, including DS. SCN1A encodes the voltage-gated sodium channel Nav1.1, while SCN1B encodes the protein β1. Although they exhibit very different cell physiology phenotypes, disruption of Scn1a or Scn1b in mice causes epilepsy phenotypes similar to DS patients. While movement abnormalities have been noted in both of these DS mouse models, these comorbidities have not been fully quantified for comparison with the onset of other developmental and neurological deficits or studied mechanistically. The purpose of our study was to define the natural history of movement and gait abnormalities in two distinct mouse models of DS.

Methods: We used two validated genetic mouse models of DS for these studies. Scn1a experimental mice were produced by crossing an Scn1a+/-;129 (congenic 129S6/SvEvTac background) mouse with a wild type C57Bl/6J. The resulting Scn1a+/-;129/C57 pups were compared with Scn1a+/+;129/C57 littermate controls. Scn1b experimental mice were produced by crossing Scn1b+/-;C57 mice (on a congenic C57Bl/6J background). Scn1b-/-;C57 mice were compared with Scn1b+/+;C57 littermate controls.

We measured gait and motor coordination by video-recording mice moving freely in an open arena, across development from postnatal ages (P) 2-24. We used the software DeepLabCut to track the movements of the mice. We then used Python to analyze body posture, head movements, step size and walking velocity, and the ability to manipulate food treats and objects. We quantified differences in behavior between genotypes across ages.

Results: We found that experimental mice of both models have abnormal gait and reduced walking speed compared to the WT littermates. Further analysis will examine whether these motor dysfunctions follow a pattern of developmental delay, arrest, or regression.

Conclusions: Our data shows that both DS mouse models exhibit signs of movement disorders early in development. These changes in behavior further validate these models as predictive of both epilepsy and other neurological comorbidities exhibited by DS patients.

Funding: Please list any funding that was received in support of this abstract.: This work was supported by fellowships from both the Women in Neuroscience Foundation and the UT Austin Texas Institute for Discovery Education in Science (TIDES) to Samantha Jackson, and by NIH R01 NS122500.