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bioRxiv · 10.1101/2024.11.19.624370

A novel mouse model for developmental and epileptic encephalopathy by Purkinje cell-specific deletion of Scn1b

Guillen, F. I.·Geist, M. A.·Cheng, S.-Y.·Harris, A. M.·Trevino, M. E.·Brumback, A. C.·Nishiyama, H.·Howard, M. A.
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Abstract

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 knockout of Scn1b, globally and even in some cell-specific models (e.g., Parvalbumin+ interneuron-specific knockout) in adult mice, leads to severe and progressive epilepsy, health deterioration, and 100% mortality within weeks. Here, we report findings of a novel transgenic mouse line in which Scn1b was specifically deleted in cerebellar Purkinje cells. Unlike most existing models, these mice did not show failure to thrive or early mortality. However, we quantified marked decrements to Purkinje cell physiology as well as motor, social, and cognitive dysfunction. Our data indicate 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.

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Guillen, F. I., Geist, M. A., Cheng, S.-Y., Harris, A. M., Trevino, M. E., Brumback, A. C., Nishiyama, H., Howard, M. A.. 2024-11-19. A novel mouse model for developmental and epileptic encephalopathy by Purkinje cell-specific deletion of Scn1b. https://doi.org/10.1101/2024.11.19.624370

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