Evidence map›Paper›PMID 42530523›Full record

ArticleEpilepsia2026

Epilepsy-associated SCN2A-L1342P mutation drives network hyperexcitability and widespread transcriptomic changes in human cortical organoids.

Maria I Olivero-Acosta, Morgan Robinson, Zhefu Que, Zaiyang Zhang, Karen V Salazar-Salazar, Hope Elizabeth Harlow, Vinayak Shankar, Seoyeon Hong, Muhan Wang, Conrad M Otterbacher and 17 more

Abstract read
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In one paragraph

Article in Epilepsia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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2 · The registry

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3 · Its place in the literature

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

27 authors.

Maria I Olivero-AcostaBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.ORCID https://orcid.org/0000-0002-2799-7336
Morgan RobinsonBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.ORCID https://orcid.org/0000-0003-4719-196X
Zhefu QueBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Zaiyang ZhangBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Karen V Salazar-SalazarBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Hope Elizabeth HarlowBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Vinayak ShankarBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Seoyeon HongBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Muhan WangBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Conrad M OtterbacherBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Hina KadonoBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Manasi HalurkarBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.ORCID https://orcid.org/0000-0003-0936-6925
Harish KothandaramanPurdue University Institute for Cancer Research, Purdue University, West Lafayette, Indiana, USA.
Nadia Atallah LanmanDepartment of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA.
Trang NguyenBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Kyle WettschurackBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Benjamin ZirkleBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Layan YunisBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Ningren CuiBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Xiaoling ChenBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Jingliang ZhangBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
Jiaxiang WuBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.
William C SkarnesCellular Engineering, The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.
Chongli YuanDavidson School of Chemical Engineering, Purdue University, West Lafayette, Indiana, USA.
Feng GuoDepartment of Intelligent Systems Engineering, Indiana University, Bloomington, Indiana, USA.
Megan AbbottPediatric Neurology, University of Colorado School of Medicine, Aurora, Colorado, USA.ORCID https://orcid.org/0009-0007-8692-0770
Yang YangBorch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA.ORCID https://orcid.org/0000-0001-6417-3654

Funding

Neuronal and Behavioral Deficits Associated with Scn2a Deficiency in Autism Spectrum DisorderR01NS117585 · NINDS · PURDUE UNIVERSITY · PI YANG, YANG · 2021 to 2025
$2.0M
Neuronal hyperexcitability and seizures in a Scn2a deficient mouse modelR01NS123154 · NINDS · PURDUE UNIVERSITY · PI YANG, YANG · 2021 to 2025
$1.9M
NIH HHS NS117585NIH HHS NS123154NINDS NIH HHS R01 NS117585NINDS NIH HHS R01 NS123154
6 · The paper itself

Abstract

objectiveSCN2A pathogenic mutations, such as the recurrent heterozygous Nav1.2-L1342P, are monogenic causes of epilepsy. In this human-induced pluripotent stem cell-derived model system, we aim to investigate the molecular and cellular mechanisms underlying SCN2A-L1342P-associated pathology.

methodsUsing a human male induced pluripotent stem cell (iPSC) reference line (KOLF) carrying the Nav1.2-L1342P mutation, we generated three-dimensional (3D) cortical organoids for functional studies. Patch-clamp, multi-electrode array (MEA) recordings, immunocytochemistry, and RNA sequencing were used to characterize the disease phenotypes.

resultsNav1.2-L1342P organoid neurons displayed increased intrinsic excitability and amplified excitatory post-synaptic currents, which are consistent with an increase in excitatory synapse formation revealed by SYN1/PSD95 immunostaining. Moreover, elevated network firing activity, as demonstrated by MEA, indicates a pronounced network hyperexcitability. Transcriptomic profiling of organoids carrying the Nav1.2-L1342P mutation further revealed significant alterations in synaptic, glutamatergic, developmental, and senescence/apoptotic pathways. SIGNIFICANCE: Our findings demonstrate that the Nav1.2-L1342P mutation drives a multifaceted disease phenotype, including network hyperexcitability and disruption of pathways related to neuronal and synaptic functions. These results advance our understanding of SCN2A-related developmental and epileptic encephalopathy (DEE), laying a foundation for personalized interventions.

Indexed as

Cerebral CortexEpilepsyNAV1.2 Voltage-Gated Sodium ChannelOrganoidsTranscriptomeHumansInduced Pluripotent Stem CellsMaleMutationNeuronsPatch-Clamp TechniquesNAV1.2 Voltage-Gated Sodium ChannelSCN2A protein, humancortical organoidsL1342Pmulti‐electrode arraySCN2Avoltage‐gated sodium channel Nav1.2

Identifiers

PMID42530523
PMCPMC13675769

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