Background
Sanfilippo syndrome (MPS IIIA) is a form of childhood dementia that leads to progressive cognitive decline, loss of skills, and premature death. In this study, researchers used patient-derived stem cells to model human brain networks. They found that early disease changes are driven by disrupted communication between brain cells, where an imbalance between activating (“go”) and regulating (“stop”) signals leads to overactive neural circuits over time. By capturing these early changes in human cells, this research provides clearer insight into how the disease begins and highlights the value of human-based, non-animal models in studying complex neurological conditions.
Article
Mazzachi, P., McDonald, E., Greenberg, Z., Noreña Puerta, A., Tran, J., Inushi De Silva, M., Christensen, C., Adams, R., Loskarn, S., Beard, H., Zabolocki, M., Elmasri, M., Maack, M., Elvidge, K.L., Hutchinson, M.R., O’Neill, C., Hemsley, K.M., Melton, L., Smith, N. and Bardy, C. (2026) Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks. Nature Communications, 17, 3161. Available at: https://doi.org/10.1038/s41467-026-71112-9
Authors
Mazzachi, P., McDonald, E., Greenberg, Z., Noreña Puerta, A., Tran, J., Inushi De Silva, M., Christensen, C., Adams, R., Loskarn, S., Beard, H., Zabolocki, M., Elmasri, M., Maack, M., Elvidge, K.L., Hutchinson, M.R., O’Neill, C., Hemsley, K.M., Melton, L., Smith, N. and Bardy, C.
Affiliations
- South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia
- Flinders University, Adelaide, Australia
- Adelaide University, Adelaide, Australia
- Women’s and Children’s Health Network, Adelaide, Australia
- Sanfilippo Children’s Foundation, Australia
- Childhood Dementia Initiative, Australia
- Cure Sanfilippo Foundation, USA
- Brain Organoid Therapeutics, Australia
Funders
- Australian Medical Research Future Fund (via the Accelerated Research Program and the Stem Cell Therapies Mission)
- Australian Research Council (via Future Fellowships).
- Sanfilippo Children’s Foundation
- Women’s and Children’s Hospital Foundation (through the Malcolm Douglas Grant Research Fund)
- Boileau Corporate Philanthropy
- The Grosset Gaya Fund
- Australian Government Research Training Program Scholarship
- Flinders University Research Scholarship
- Flinders Health and Medical Research Institute PhD Scholarship Program
- South Australian Health and Medical Research Institute BRIGHT Sparks Award.
- BioPlatforms Australia as part of the National Collaborative Research Infrastructure Strategy
Aim
To investigate how Sanfilippo syndrome (MPS IIIA), a form of childhood dementia, affects communication between brain cells, and to identify early functional changes using human-derived neural models.
Terminology
- Induced pluripotent stem cells (iPSCs): Adult cells (such as skin cells) reprogrammed into a stem cell state, allowing them to develop into different cell types, including neurons
- Cortical neurons: Brain cells involved in thinking, memory, and behaviour
- Synapse: The connection point where neurons send and receive signals
- Excitatory signalling (“go” signals): Signals that increase brain activity by encouraging neurons to fire
- Inhibitory signalling (“stop” signals): Signals that regulate or dampen brain activity, preventing overactivation
- Excitatory/Inhibitory (E/I) balance: The balance between activating and regulating signals in the brain, essential for normal function
- Patch-clamping: A technique used to measure electrical activity in individual neurons
- Multielectrode arrays (MEA): A method that records electrical activity across networks of neurons simultaneously
- Action potential: An electrical signal that allows neurons to communicate
- Neural network activity: The coordinated activity of groups of neurons
Methods
- Skin cells from children with MPS IIIA and healthy donors were reprogrammed into induced pluripotent stem cells and differentiated into cortical neurons
- These neurons were grown into functional neural networks in vitro, enabling researchers to model disease-relevant brain activity in a human system over time
- Researchers assessed:
- Electrical activity of individual neurons (patch-clamping)
- Network-level activity (multielectrode arrays)
- Synapse structure and density
- Gene activity within cells
Results
Findings indicate that early disease changes are driven by disruptions in neural communication, rather than visible structural damage to brain cells.
Results show neurons appeared structurally normal, with no major differences in size, shape, or development between patient and healthy cells. Individual neurons were also able to generate electrical signals normally. However, differences emerged in how neurons communicated:
- Signals that activate brain activity (“go” signals) were increased in patient-derived neurons
- Signals that regulate and dampen activity (“stop” signals) were not proportionally increased
- This created an imbalance between activation and regulation in neural networks
At the network level
- Neural circuits became more active overall with:
- Increased numbers of active neurons
- More frequent bursts of activity
- More neurons were firing together at the same time, rather than in a balanced and controlled pattern
At a molecular level
- Changes were observed in genes involved in synaptic function, particularly those associated with excitatory signalling
Conclusion
Sanfilippo syndrome (MPS IIIA) is a form of childhood dementia with severe and progressive impacts on children, affecting their memory, behaviour, and overall neurological function. This study shows that childhood dementia is associated with early disruptions in how brain cells communicate, rather than immediate structural damage.
Specifically, an imbalance between activating and regulating signals leads to increasingly overactive neural networks over time. These findings provide important insight into the early mechanisms driving disease progression and offer a clearer direction for future research into potential therapeutic approaches. Importantly, these insights were made possible through human-derived models, highlighting the value of human-relevant methods in studying complex neurological conditions.
Relevance
Animal models have traditionally been used to study neurological diseases, but they can be limited in capturing human brain function—particularly when it comes to neural network activity and cognition.
Historically, neuroscience research has often relied on invasive animal models, including studies where brain regions are surgically altered in primates to observe changes in behaviour. An example of an experiment using non-human primates to research human brain function is here.
In contrast, this present study demonstrates how human-derived neural models can be used to investigate brain function and dysfunction directly, without the need for such approaches. This study uses neural models developed from patient cells, which are reprogrammed into brain cells and grown into functional networks. This allows researchers to directly observe disease-related changes, including early disruptions in how brain cells communicate that may not be visible when looking only at cell structure.
By enabling the study of early disease processes directly in human neural systems, this approach provides insight into mechanisms that may otherwise be difficult to detect.
More broadly, this reflects a shift toward methods that are both human-relevant and ethically responsive, generating meaningful data while avoiding the need for animal use. It highlights how advances in human-based models can support more accurate and translatable research, particularly in complex neurological conditions.