# Role of SCN1B in Inherited Epilepsy

> **NIH NIH R37** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $653,145

## Abstract

ABSTRACT:
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) α and β 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 β1 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...

## Key facts

- **NIH application ID:** 9853843
- **Project number:** 5R37NS076752-08
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Lori L. Isom
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $653,145
- **Award type:** 5
- **Project period:** 2011-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853843

## Citation

> US National Institutes of Health, RePORTER application 9853843, Role of SCN1B in Inherited Epilepsy (5R37NS076752-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9853843. Licensed CC0.

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