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

Area of Science:

• Neuroscience
• Stem Cell Biology
• Genetics

Background:

• Synaptic homeostasis alterations are implicated in brain disorders.
• Childhood dementia, specifically Mucopolysaccharidosis Type IIIA (MPS IIIA), exhibits poorly understood synaptic dysfunction.
• MPS IIIA is a common form of childhood-onset dementia.

Purpose of the Study:

• To investigate synaptic dysfunction in human cortical circuits derived from MPS IIIA patients.
• To identify neurophysiological phenotypes associated with childhood dementia using in vitro models.
• To support drug discovery targeting synaptic dysfunction for cognitive improvement in MPS IIIA.

Main Methods:

• Generation of human cortical circuits from induced pluripotent stem cells (iPSCs) of MPS IIIA donors.
• Assessment of action potential firing capacity and neuronal morphology.
• Long-term neural maturation studies to analyze network dynamics and gene expression.

Main Results:

• MPS IIIA neurons exhibit normal action potential firing and morphology initially.
• Long-term maturation reveals excitation/inhibition imbalances due to hyperactive excitatory synapses.
• Disrupted network dynamics and dysregulated gene expression linked to synaptic homeostasis were observed.

Conclusions:

• In vitro human neural models effectively detect neurophysiological phenotypes in childhood dementias.
• Synaptic dysfunction, particularly excitation/inhibition imbalance, is a key feature of MPS IIIA.
• Targeting synaptic dysfunction offers a promising strategy for improving cognition in MPS IIIA and related disorders.