Developmental instability of CA1 pyramidal cells in Dravet Syndrome

Dravet Syndrome (DS) is mostly caused by heterozygous loss-of-function mutations in the voltage-gated sodium channel SCN1A (Nav1.1), thought to result in severe epilepsy and neurodevelopmental impairment due to reduced interneuron excitability. Recent studies in mouse models suggest that an "interneuronopathy" alone does not completely explain all the cellular and network impairments seen in DS. Here, we investigated the development of the intrinsic, synaptic, and network properties of CA1 pyramidal cells in a DS model prior to the appearance of overt seizures. We report that CA1 pyramidal cell development is disrupted by loss of Scn1a, and propose that this is explained by a period of reduced intrinsic excitability in early postnatal life, during which Scn1a is normally expressed in hippocampal pyramidal cells. We also use a novel ex vivo model of homeostatic plasticity to show an instability in homeostatic response during DS epileptogenesis. This study provides evidence for an important role of Scn1a haploinsufficiency in pyramidal cells in the pathophysiology of DS.