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.