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bioRxiv · 10.1101/2021.07.28.454042

Developmentally-regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome

Kaneko, K.·Currin, C. B.·Goff, K. M.·Somarowthu, A.·Vogels, T. P.·Goldberg, E. M.
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Abstract

Dravet syndrome (DS) is a neurodevelopmental disorder defined by epilepsy, intellectual disability, and sudden death, due to heterozygous variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from pre-weanling Scn1a+/- mice show impaired action potential generation. A novel approach assessing PV-IN function in the same mice at two developmental time points showed that, at post-natal day (P) 16-21, spike generation was impaired all mice, deceased prior or surviving to P35. However, synaptic transmission was selectively dysfunctional in pre-weanling mice that did not survive. Spike generation in surviving mice normalized by P35, yet we again identified abnormalities in synaptic transmission. We conclude that combined dysfunction of PV-IN spike generation and synaptic transmission drives disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology. Modeling revealed that PV-IN axonal propagation is more sensitive to decreases in sodium conductance than spike generation.

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Kaneko, K., Currin, C. B., Goff, K. M., Somarowthu, A., Vogels, T. P., Goldberg, E. M.. 2021-07-28. Developmentally-regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome. https://doi.org/10.1101/2021.07.28.454042

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