# Hippocampal Circuit Dysfunction in SCN8A Gain-of-Function Encephalopathy

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $429,000

## Abstract

PROJECT SUMMARY / ABSTRACT
Developmental epileptic encephalopathy (DEE) is a complex disorder characterized by refractory seizures,
developmental delay, cognitive disabilities, movement disorders and elevated risk of sudden unexpected death
(SUDEP) (1-4). De novo missense mutations in the sodium channel gene SCN8A have been identified in more
than 300 patients with DEE, resulting in the disorder early infantile epileptic encephalopathy 13 (EIEE13;
OMIM #614558) or SCN8A encephalopathy (3). We have reported that the most common pathogenic
mechanism of SCN8A encephalopathy is gain-of-function (GOF) changes in sodium channel Nav1.6. We
developed a mouse model with expression of the patient mutation p.Arg1872Trp (R1872W) that is dependent
on Cre-induced recombination (5). This model allows seizures to be induced in a controlled fashion in the adult
animal, bypassing the early lethality of constitutively expressed mutations. By crossing conditional R1872W
mice with CAG-Cre-ER mice expressing a tamoxifen-inducible Cre transgene, we can induce spontaneous
seizures in adult mice that recapitulate patient phenotypes. The identical genetic background of these congenic
mice contributes to experimental reproducibility.
Hippocampal ripples are fast oscillations seen during non-REM (NREM) sleep and quiet wakefulness. Behavioral
activity patterns, such as the sequential firing of hippocampal place cells during navigation, are replayed in a
compressed neural sequence during ripples, helping to consolidate related memories. Ripples are impaired in a
multitude of epilepsies, likely contributing to memory and cognitive deficits in patients. While healthy and
pathological ripple dynamics are well studied in temporal lobe epilepsy and more recently in a global SCN1A
haploinsufficiency model, there is a gap in knowledge regarding the impact on ripples of SCN8A
encephalopathies. It is therefore important to investigate the effects of SCN8A encephalopathy on ripples and
other hippocampal circuit output. Our central hypothesis is that both ripples (Aim 1) and hippocampal place cell
firing (Aim 2) are progressively impaired during the development of SCN8A encephalopathy. The rationale for
this hypothesis comes from our published observations that patient mutations cause elevated activity of Nav1.6
channels due to premature activation or impaired inactivation, resulting in hyperactivity of cultured hippocampal
pyramidal cells. The completion of these Aims will result in the collection of massive datasets that will be shared
with the epilepsy community, allowing for community-wide dissection of seizure and interictal dynamics, seizure-
onset and SUDEP prediction algorithms, as well as changes in sleep-wake rhythms over time. The observed
changes in hippocampal circuit dynamics will generate further hypotheses that can be dissected using cell type-
and region-specific CRE transgenes in a follow-up R01 application.

## Key facts

- **NIH application ID:** 10196478
- **Project number:** 1R21NS121700-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Omar Jamil Ahmed
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196478

## Citation

> US National Institutes of Health, RePORTER application 10196478, Hippocampal Circuit Dysfunction in SCN8A Gain-of-Function Encephalopathy (1R21NS121700-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10196478. Licensed CC0.

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