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STX1B variant-specific synaptic dysfunction is associated with network hyperexcitability in human iPSC-derived neurons.

Overview

Authors: Carolin Haag1, Felix Gsell1, Oleg Vinogradov1, Morgana Barroso Oquendo2, Yuanyuan Liu1, Betül Uysal1, Heidi Löffler1, Fabienne Stehle1, Fabian Klopfer1, Jan Crönlein1, Kaja Böttcher1, Ruud F. Toonen3, Hiltrud Muhle4, Bernhard Kohl5, Holger Lerche1, Niklas Schwarz1
ORCID iDs: Morgana Barroso Oquendo, Niklas Schwarz
  1. Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  2. Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany
  3. Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
  4. Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany
  5. Department of Neuropediatrics, Hamburg Epilepsy Center, Catholic Children's Hospital Wilhelmstift, Hamburg, Germany
Institutions: Hertie Institute for Clinical Brain Research (Germany); University of Tübingen (Germany); Quantitative Biology Center; Vrije Universiteit Amsterdam (Netherlands); University Hospital Schleswig-Holstein (Germany); Katholisches Kinderkrankenhaus Wilhelmstift (Germany)
Journal: EBioMedicine, volume 131, article 106451
Dates: received 28 August 2025; accepted 10 August 2026; published online 31 August 2026; in print September 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.ebiom.2026.106451 · PMID 42673765 · PMCID PMC13560554 · OpenAlex W7204837246
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), epilepsy (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Smoothing, state filtering, decompositions, Preprocessing, Evoked potentials, Single-unit activity, calcium imaging
Keywords: STX1B, Epilepsy, Induced pluripotent stem cells, Disease modelling, Synaptic transmission
MeSH: Induced Pluripotent Stem Cells*, Neurons*, Synapses*, Syntaxin 1*, Gene Expression Profiling, Humans, Synaptic Transmission (* major topic)
Topic: Neuroscience and Neuropharmacology Research (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex
Funding: Federation of European Biochemical Societies; Faculty of Medicine Tübingen; Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research); Else Kröner Fresenius Stiftung; Open Access Publishing; University of Tübingen
Citations: not cited yet (Europe PMC); 61 references in the paper
Research resources: goat anti-mouse RRID:AB_11125936, RRID:AB_143157, RRID:AB_143165, mouse anti-Bassoon RRID:AB_1659573, in combination with chicken anti-MAP2 RRID:AB_2138153, RRID:AB_2200400, rabbit anti-SOX2 RRID:AB_2341193, RRID:AB_2534069, RRID:AB_2534072, RRID:AB_2534096, RRID:AB_2535866, RRID:AB_2866491, goat anti-rabbit RRID:AB_3752686, goat anti-chicken RRID:AB_430845, RRID:AB_445175, mouse anti-Vinculin RRID:AB_477629, mouse anti-SSEA4 RRID:AB_778073, mouse anti-TRA-1-60 RRID:AB_778563, RRID:AB_887730, rabbit anti-STX1B RRID:AB_887900

Abstract

Background: Variants in STX1B/syntaxin-1B are linked to a spectrum of fever-associated epilepsy syndromes. While studies in murine models have provided mechanistic insights, their relevance to human disease in a heterozygous context may be limited.

Methods: We investigated two pathogenic STX1B variants using isolated single neurons and neuronal network cultures derived from patient-specific induced pluripotent stem cells. These carried either a de novo p.G226R variant, associated with severe developmental epilepsy, or an InDel variant (p.K45delinsRCMIE/p.L46M) linked to a transient familial seizure syndrome. Synaptic function and network excitability were assessed using patch-clamp and multi-electrode array recordings, alongside morphological and transcriptomic profiling.

Findings: G226R exhibited both gain- and loss-of-function characteristics, with increased miniature excitatory postsynaptic current frequency in networks but not in autapses, and synaptic failure during sustained high-frequency stimulation. For the InDel variant, the predicted loss-of-function phenotype based on reduced syntaxin-1B levels was not detectable at the single-cell level, likely masked by compensatory synaptic upregulation. At the network level, however, both variants were associated with neuronal hyperexcitability, characterised by more frequent and prolonged bursting activity, with a much stronger phenotype in G226R-containing networks. Transcriptomic profiling revealed a differential dysregulation of synaptic and other neuronal genes.

Interpretation: The divergence between morphological, electrophysiological and transcriptomic findings suggests that compensatory mechanisms may contribute to network hyperexcitability. Initially engaged to maintain homoeostasis, they may ultimately contribute to a pathological network state. The graded severity of network alterations across STX1B variants correlates with the clinical phenotypes.

Funding: BMBF (Treat ION-01GM2210A, SNAREopathies-01EW1809A), 2023 FEBS Summer Fellowship, Fortüne programme (2610-0-0), EKFS college precise.net, Open Access Publishing Fund of University of Tübingen.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

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Data

Datasets cited

Data sharing statement

The bulk RNA sequencing dataset generated during this study has been deposited in NCBI's Gene Expression Omnibus and is publicly accessible through the GEO Series accession number GSE329848.

All other de-identified quantitative datasets underlying the findings of this study, including single-cell patch-clamp recordings, multi-electrode array (MEA) data metrics, and immunofluorescence quantification matrices, are available from the corresponding authors upon reasonable request for the purpose of scientific replication.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Morgana Barroso Oquendo (0000-0003-4221-5723); Niklas Schwarz (0000-0002-4064-3073); removed Morgana Barroso Oquendo; Niklas Schwarz

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 16 authors, 5 keywords, 7 MeSH terms, 6 funders, 57 references, 20 RRIDs.

Cite

This paper

Haag, C., Gsell, F., Vinogradov, O., Oquendo, M. B., Liu, Y., Uysal, B., Löffler, H., Stehle, F., Klopfer, F., Crönlein, J., Böttcher, K., Toonen, R. F., Muhle, H., Kohl, B., Lerche, H., & Schwarz, N. (2026). STX1B variant-specific synaptic dysfunction is associated with network hyperexcitability in human iPSC-derived neurons. EBioMedicine, 131, 106451. https://doi.org/10.1016/j.ebiom.2026.106451

BibTeX

@article{haag2026stx1b,
author = {Haag, Carolin and Gsell, Felix and Vinogradov, Oleg and Oquendo, Morgana Barroso and Liu, Yuanyuan and Uysal, Betül and Löffler, Heidi and Stehle, Fabienne and Klopfer, Fabian and Crönlein, Jan and Böttcher, Kaja and Toonen, Ruud F. and Muhle, Hiltrud and Kohl, Bernhard and Lerche, Holger and Schwarz, Niklas},
title = {{STX1B variant-specific synaptic dysfunction is associated with network hyperexcitability in human iPSC-derived neurons}},
journal = {EBioMedicine},
year = {2026},
month = aug,
volume = {131},
pages = {106451},
publisher = {Elsevier},
issn = {2352-3964},
doi = {10.1016/j.ebiom.2026.106451},
url = {https://doi.org/10.1016/j.ebiom.2026.106451},
pmid = {42673765},
pmcid = {PMC13560554}
}

RIS

TY - JOUR
AU - Haag, Carolin
AU - Gsell, Felix
AU - Vinogradov, Oleg
AU - Oquendo, Morgana Barroso
AU - Liu, Yuanyuan
AU - Uysal, Betül
AU - Löffler, Heidi
AU - Stehle, Fabienne
AU - Klopfer, Fabian
AU - Crönlein, Jan
AU - Böttcher, Kaja
AU - Toonen, Ruud F.
AU - Muhle, Hiltrud
AU - Kohl, Bernhard
AU - Lerche, Holger
AU - Schwarz, Niklas
TI - STX1B variant-specific synaptic dysfunction is associated with network hyperexcitability in human iPSC-derived neurons
T2 - EBioMedicine
J2 - eBioMedicine
PY - 2026
DA - 2026/08/31
VL - 131
SP - 106451
SN - 2352-3964
PB - Elsevier
DO - 10.1016/j.ebiom.2026.106451
UR - https://doi.org/10.1016/j.ebiom.2026.106451
LA - en
ER -

CSL-JSON

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