Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks
Alterations in synaptic homeostasis are linked to cognitive and behavioural impairments in brain disorders. However, synaptic dysfunction in childhood dementia is poorly understood. Here, we generate human cortical circuits from induced pluripotent stem cells (iPSCs) derived from donors with Mucopolysaccharidosis Type IIIA (MPS IIIA), also known as Sanfilippo syndrome, a common form of childhood-onset dementia. Action potential firing capacity and morphology of MPS IIIA patient neurons in culture are similar to those of neurons from neurotypical donors. However, long-term neural maturation reveals excitation/inhibition imbalances caused by hyperactive excitatory synapses, disrupted network dynamics, and dysregulated gene expression linked to synaptic homeostasis. This study validates in vitro human neural models to detect neurophysiological phenotypes in childhood dementias and supports drug discovery strategies that target synaptic dysfunction to improve cognition in MPS IIIA and related brain disorders.
Authors
- Cara O’Neill (ORCID: https://orcid.org/0000-0002-9377-259X)
- Zarina Greenberg (ORCID: https://orcid.org/0000-0002-0103-8321)
- Manam Inushi De Silva (ORCID: https://orcid.org/0000-0002-5517-5903)
- Lisa Melton (ORCID: https://orcid.org/0000-0002-6314-359X)
- Kim M. Hemsley (ORCID: https://orcid.org/0000-0003-1038-9884)
- Jenne Tran
- Megan Maack (ORCID: https://orcid.org/0000-0003-0870-0338)
- Mark R. Hutchinson (ORCID: https://orcid.org/0000-0003-2154-5950)
- Helen Beard (ORCID: https://orcid.org/0000-0003-2042-1438)
- Kristina L. Elvidge (ORCID: https://orcid.org/0000-0002-9763-344X)
- Mary Elmasri
- Cédric Bardy (ORCID: https://orcid.org/0000-0001-8321-0852)
- Paris Mazzachi (ORCID: https://orcid.org/0009-0006-5974-7901)
- Michael Zabolocki (ORCID: https://orcid.org/0000-0002-1856-5523)
- Alejandra Noreña Puerta (ORCID: https://orcid.org/0009-0001-9531-1180)
- Sebastian Loskarn
- R. Adams
- Cade Christensen
- Ella McDonald
- Nicholas Smith
Institutions
- Flinders University (AU)
- Women's and Children's Health Network (AU)
- SA Health (AU)
- Children’s Foundation (GB)
- South Australian Health and Medical Research Institute (AU)
- The University of Adelaide (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-07
- DOI
- https://doi.org/10.1038/s41467-026-71112-9
- Primary Topic
- Lysosomal Storage Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- South Australian Health and Medical Research Institute
- Children's Hospital Foundation
- Australian Government
- Flinders University
- Australian Research Council
- National Health and Medical Research Council