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Updated: Dec 31, 2025

A Behavioral Screen for Heat-Induced Seizures in Mouse Models of Epilepsy

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Published on: July 12, 2021

SCN8A encephalopathy: Mechanisms and models.

Miriam H Meisler¹

¹Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.

|January 7, 2020

Summary

De novo SCN8A mutations cause epileptic encephalopathy by increasing neuronal excitability. Mouse models of these mutations aid in developing new therapies for this severe neurological disorder.

Area of Science:

Neuroscience
Genetics
Pharmacology

Background:

De novo mutations in the SCN8A gene are implicated in approximately 2% of epileptic encephalopathy cases.
These mutations affect the Nav1.6 sodium channel, leading to neuronal hyperexcitability and seizures.

Purpose of the Study:

To investigate the in vivo effects of patient-derived SCN8A mutations (N1768D and R1872W) on neuronal function.
To establish and utilize mouse models for preclinical drug testing in SCN8A-associated epilepsy.

Main Methods:

Generation of two mouse models with specific SCN8A missense mutations (N1768D and R1872W).
Utilized a conditional knockout strategy for the R1872W mutation to study its effects across different neuronal types and developmental stages.
Performed in vivo characterization of neuronal function and preclinical drug testing.

Keywords:

SCN8A encephalopathy mouse model mutation sodium channel

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Main Results:

The generated mouse models recapitulate key aspects of SCN8A-related epileptic encephalopathy.
Demonstrated that SCN8A mutations alter biophysical properties of Nav1.6, causing neuronal hyperexcitability.
Preclinical testing in these models supports the efficacy of potential new therapeutic strategies.

Conclusions:

SCN8A mutations are a significant cause of early-onset epileptic encephalopathy.
Mouse models are crucial for understanding the pathophysiology and developing treatments for SCN8A channelopathies.
Loss-of-function SCN8A mutations are linked to intellectual disability, highlighting the diverse roles of this gene.