Early onset pediatric epileptic encephalopathies such as Dravet Syndrome (DS) are devastating to families because of the high degree of neurodevelopmental compromise, including developmental delay, cognitive decline, and intellectual disability. Most concerning are the severe seizures and high risk of sudden unexpected death in epilepsy (SUDEP). Mutations in voltage-gated Na+ channel (VGSC) ? and ? subunit genes are linked to DS. While the majority of DS cases are linked to SCN1A haploinsufficiency, SCN1B homozygous mutations are also linked to DS. Scn1b-/- mice have a DS phenotype with SUDEP. SCN1B encodes VGSC ?1 subunits, which are developmentally regulated cell adhesion molecules and ion channel modulators that play critical roles in the regulation of excitability. Scn1b-/- mice have cell type specific changes in Na+ (INa) and K+ (IK) currents. In addition, Scn1b-/- mice have neuronal proliferation, migration, and pathfinding defects at postnatal day (P)5 that precede seizure onset at ~P10. These data suggested that alterations in CAM function may contribute to hyperexcitability, however, new data challenge this idea and offer the alternative explanation that defective cell adhesion in SCN1B-linked DS may not contribute to seizures but instead impact other co-morbidities. Preliminary data show that Scn1b-/- mice also have delayed maturation of neuronal Cl- gradients such that GABAergic signaling remains depolarizing and excitatory until ~P17-18, which may contribute to hyperexcitability in SCN1B-linked DS. The objective of this work is to understand the mechanism of hyperexcitability in SCN1B-linked DS. The central hypothesis is that the mechanism of hyperexcitability in the Scn1b-/- model of DS is cell type specific changes in INa, IK, and GABAergic signaling. Further, it is proposed that human SCN1B-DS mutations result in loss-of-function, with similar defects in ionic currents and delayed maturation of GABAergic signaling as observed in Scn1b-/- neurons. The experimental plan will test three Aims: 1. To determine the mechanism of hyperexcitability resulting from Scn1b deletion; 2. To determine whether human SCN1B-linked DS mutations result in loss-of-function in mouse models; 3. To determine the phenotype of SCN1B-linked DS patient-derived induced pluripotent stem cell (iPSC) neurons. Model choice is key to understanding epilepsy mechanisms. Importantly, mice are not small humans. Thus, patient-derived iPSC neuronal models provide essential information regarding human disease. On the other hand, mature brain networks cannot yet be replicated using iPSCs and so brain slice preparations from transgenic mouse models remain important to understanding circuitry. Rather than relying on a single model, this project will compare and contrast human and mouse models to understand key mechanistic aspects of the development of hyperexcitability in DS. Even though SCN1B-linked DS is rare compared to SCN1A-linked disease, this work may lead to the discovery of novel targets for therapeutic intervention in DS caused by multiple types of gene mutations.
Early onset pediatric epileptic encephalopathies such as Dravet Syndrome (DS) are devastating to families because of the high degree of neurodevelopmental compromise, including developmental delay, cognitive decline, and intellectual disability. Most concerning are the severe seizures and high risk of sudden unexpected death in epilepsy (SUDEP). Mutations in voltage-gated Na+ channel ? and ? subunit genes are linked to DS. While the majority of DS cases are linked to SCN1A haploinsufficiency, SCN1B homozygous mutations are also linked to DS. The objective of this work is to understand the mechanism of hyperexcitability in human SCN1B-linked DS. Even though SCN1B-linked DS is a rare disease, this work is important because it will provide new information regarding how deficits in brain development and regulation of ionic currents can synergize to result in hyperexcitability.
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