Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks

Topic: Brain proteins, microglia and lab models

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. Here authors show in a human stem cell–derived model, neural cultures from children with MPSIIIA exhibit hyperactive excitatory synapses associated with excitation–inhibition imbalance, altered network dynamics, and broad dysregulation of genes involved in synaptic homeostasis.

Key findings

• Here authors show in a human stem cell–derived model, neural cultures from children with MPSIIIA exhibit hyperactive excitatory synapses associated with excitation–inhibition imbalance, altered network dynamics, and broad dysregulation of genes involved in synaptic homeostasis.

Why it matters

In human stem cell-derived neural cultures from children with Sanfilippo syndrome, a childhood dementia, the authors found hyperactive excitatory synapses and related gene dysregulation. The work is an in vitro model and supports drug discovery strategies targeting synaptic dysfunction, not a treatment or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41467-026-71112-9
• PubMed: 41946741
• Original source →
• Free full text: Nature Communications →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{mazzachi2026-41946741,
  author  = {Mazzachi, Paris and McDonald, Ella and Greenberg, Zarina and Puerta, Alejandra Noreña and Tran, Jenne and De Silva, Manam Inushi and Christensen, Cade and Adams, Robert and others},
  title   = {{Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks}},
  journal = {Nature Communications},
  year    = {2026},
  doi     = {10.1038/s41467-026-71112-9},
  pmid    = {41946741},
  url     = {https://doi.org/10.1038/s41467-026-71112-9}
}

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