Developmental dysregulation of chandelier cell excitability in a mouse model of Dravet Syndrome

Chandelier cells (ChCs) are a rare and highly specialized subtype of inhibitory neuron in the cerebral cortex that specifically and exclusively form synapses onto the axon initial segment of excitatory neurons and thereby exert powerful control of excitability. We applied a newly developed, cell type-specific enhancer element to label ChCs and assess their electrophysiological and morphological properties across development in Dravet Syndrome (<i>Scn1a</i> ^+/- mice), a prominent neurodevelopmental disorder defined by epilepsy and features of autism spectrum disorder. Dravet Syndrome is known to predominantly impact GABAergic interneurons. We found that ChCs from juvenile <i>Scn1a</i> ^+/- mice (postnatal day, P18-21) exhibit impaired excitability, and that deficits largely persist in young adulthood (P35-56). These findings are distinct from prior observations in the more common subtype of parvalbumin-positive interneurons, basket cells. We found no differences in the axonal or dendritic morphology of ChCs at either time point. Our results suggest a role for ChCs in the pathogenesis of Dravet Syndrome and constitute the first targeted study of ChC function in a specific genetically-defined neurodevelopmental disorder.