Childhood Dementia Explained by Synaptic Dysfunction, Opens New Therapies

In a new study published in Nature Communications titled, “Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks,” researchers from Flinders University in Adelaide have uncovered how hyperactive and dysregulated synaptic circuits emerge in the brain tissue of children impacted by Sanfilippo syndrome, a common form of childhood dementia. 

In Australia, an estimated 1400 children currently live with childhood dementia, with hundreds of thousands of cases worldwide. Sanfilippo syndrome is a rare genetic condition that causes fatal brain damage. Children typically reach early developmental milestones before rapidly losing cognitive skills, speech, and mobility. Early symptoms often include hyperactivity and sleep disturbance. 

Alterations in synaptic communication play key roles in neurodegenerative disease progression and cognitive decline. Yet few studies have explored how excitation and inhibition synaptic imbalances contribute to pediatric neurodegenerative disorders. 

Cedric Bardy, PhD, professor and head of the Laboratory for Human Neurophysiology and Genetics at the South Australian Health, describes the study findings as “significant progress.” Chronic overactivity in the brain appears to be a fundamental mechanism contributing to cognitive deterioration in children with Sanfilippo syndrome. 

Using human stem cell-derived cortical neurons and electrophysiology, the team demonstrated that excitatory synapses in the neurons of affected children become abnormally active during early brain development. 

While these neurons initially developed and functioned normally, they became increasingly overactive over time. Brain cell networks showed bursts of intense, highly synchronized electrical activity as they matured, mirroring the hyperactivity and neurological symptoms seen in children with the condition. 

“This hyperactivity offers a clear biological explanation for early behavioral changes, and it brings us closer to understanding the complex mechanisms contributing to childhood dementia,” said Bardy.

Results also demonstrated that these neurons are vulnerable to stress. When exposed to mild nutrient deprivation, excitatory synaptic abnormalities increased, suggesting that common illnesses or physiological stressors may accelerate neurological decline. 

“Our research shows that disrupted synaptic communication is not simply a byproduct of degeneration. It is an early driver of the disease,” Bardy says. 

Childhood Dementia Initiative CEO and founder, Megan Maack, is a co-author of the study and has been involved in guiding the project since its inception. 

“This research is significant not just for Sanfilippo syndrome, but for the field of childhood dementia as a whole,” said Maack. “By identifying the precise cellular mechanisms driving the disease, we are moving towards a personalized medicine approach—the kind of targeted treatment strategy that has transformed outcomes for children with cancer.”

Researchers are now evaluating whether drugs that are already on the market for use in other conditions could be repurposed for childhood dementia. Bardy says the team has already demonstrated that these synaptic imbalances can be corrected with certain medications in the laboratory, indicating that they represent a genuine therapeutic target. 

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