Hannan, Saad B;
Alić, Ivan;
Murray, Aoife;
Kwon, Joonhong;
Mortensen, Martin;
Kang, Hyo Jung;
Plećaš, Ante;
... Smart, Trevor G; + view all
(2026)
Synaptic and intrinsic membrane defects disrupt early neural network dynamics in Down syndrome.
Nat Commun
10.1038/s41467-025-68048-x.
(In press).
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Abstract
Down syndrome, caused by trisomy 21, affects around six million people worldwide and features learning, memory and language deficits. However, the mechanisms underlying trisomy 21 neurophenotypes involving human cortical circuitry are unknown. By characterising developing neural network dynamics and single cell excitability profiles, from synaptic and voltage-dependent ion channel behaviour using an isogenic induced pluripotent stem cell-derived neuronal model, we show that trisomy 21 impairs the activity and development of cortical circuitry. This is caused by deficient glutamatergic synaptic connectivity and by aberrant intrinsic membrane properties involving K+ and Na+ channels culminating in spike firing defects that weaken neural network activity and disrupt the synchrony of developing neurons. We also identify transiently activated A-type K+ channels, specifically Kv4.3 channels, as a key orchestrator for Down syndrome during neurodevelopment. Overall, these excitability changes will significantly contribute towards the aberrant neurophenotypes observed later on in life.
| Type: | Article |
|---|---|
| Title: | Synaptic and intrinsic membrane defects disrupt early neural network dynamics in Down syndrome |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-025-68048-x |
| Publisher version: | https://doi.org/10.1038/s41467-025-68048-x |
| Language: | English |
| Additional information: | © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10220774 |
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