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Published on: July 12, 2021
Epilepsy-associated SCN2A-L1342P mutation drives network hyperexcitability and widespread transcriptomic changes in
Maria I Olivero-Acosta1,2, Morgan Robinson1,2,3, Zhefu Que1,2
1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Epilepsia
|July 30, 2026
Summary
The Nav1.2-L1342P mutation causes epilepsy by increasing neuronal excitability and disrupting synaptic function. This study used stem cell-derived organoids to model SCN2A-related pathology and identify therapeutic targets.
Area of Science:
- Neuroscience
- Genetics
- Stem Cell Biology
Background:
- SCN2A pathogenic mutations are monogenic causes of epilepsy.
- The Nav1.2-L1342P mutation is a recurrent heterozygous mutation associated with epilepsy.
Purpose of the Study:
- To investigate the molecular and cellular mechanisms underlying SCN2A-L1342P-associated pathology using a human induced pluripotent stem cell (iPSC)-derived model.
- To characterize the disease phenotypes associated with the Nav1.2-L1342P mutation.
Main Methods:
- Generation of 3D cortical organoids from a human male iPSC line (KOLF) carrying the Nav1.2-L1342P mutation.
- Functional characterization using patch-clamp, multi-electrode array (MEA) recordings, immunocytochemistry, and RNA sequencing.
Main Results:
- Nav1.2-L1342P organoid neurons exhibited increased intrinsic excitability and amplified excitatory post-synaptic currents.
- Increased excitatory synapse formation (SYN1/PSD95 immunostaining) and pronounced network hyperexcitability (MEA recordings) were observed.
- Transcriptomic profiling revealed significant alterations in synaptic, glutamatergic, developmental, and senescence/apoptotic pathways.
Conclusions:
- The Nav1.2-L1342P mutation induces a complex phenotype including network hyperexcitability and disrupted neuronal/synaptic functions.
- This study enhances understanding of SCN2A-related developmental and epileptic encephalopathy (DEE).
- Findings provide a foundation for developing personalized therapeutic interventions for SCN2A-related disorders.
