A Novel Mouse Model for Developmental and Epileptic Encephalopathy by Purkinje Cell-Specific Deletion of Scn1b.

Loss of function variants of SCN1B are associated with a range of developmental and epileptic encephalopathies (DEEs), including Dravet syndrome. These DEEs feature a wide range of severe neurological disabilities, including changes to social, motor, mood, sleep, and cognitive function which are notoriously difficult to treat, and high rates of early mortality. While the symptomology of SCN1B-associated DEEs indicates broad changes in neural function, most research has focused on epilepsy-related brain structures and function. Mechanistic studies of SCN1B/Scn1b have delineated diverse roles in development and adult maintenance of neural function, via cell adhesion, ion channel regulation, and other intra- and extra-cellular actions. However, use of mouse models is limited as knock-out of Scn1b, globally and even in some cell-specific models (e.g., parvalbumin+ interneuron-specific knock-out) in adult mice, leads to severe and progressive epilepsy, health deterioration, and 100% mortality within weeks. Here, we report findings using male and female mice of a novel transgenic line in which Scn1b was specifically deleted in cerebellar Purkinje cells. Unlike most existing models, these mice survive and thrive. However, we quantified marked decrements to Purkinje cell physiology as well as motor, social, and cognitive dysfunction. Our data indicates that cerebellar Purkinje cells are an important node for dysfunction and neural disabilities in SCN1B-related DEEs and combined with previous work identify this as a potentially vital site for understanding mechanisms of DEEs and developing therapies that can treat these disorders holistically.