Researchers at the University of Virginia and the Salk Institute have identified a molecule whose absence may explain the faulty brain wiring seen in Down syndrome. The molecule, called pleiotrophin, appears essential for developing the connections between brain cells, and restoring it improved brain function in adult mice long after their nervous systems had fully formed.
The finding suggests a fundamentally different approach to treating Down syndrome. Unlike previous strategies that would have required intervention during narrow windows of fetal development, this method worked even after the brain had matured, opening possibilities that weren’t available before.
“This study is really exciting because it serves as proof-of-concept that we can target astrocytes, a cell type in the brain specialized for secreting synapse-modulating molecules, to rewire the brain circuitry at adult ages,” said researcher Ashley N. Brandebura, who conducted the work at the Salk Institute and is now at UVA’s School of Medicine.
A Molecule That Shapes Brain Connections
Down syndrome affects roughly 1 in 640 babies born in the United States each year. The condition, caused by an extra copy of chromosome 21, leads to intellectual disability, developmental delays, and various medical complications. Brain scans reveal that children with Down syndrome have smaller brains than typical children, with differences emerging as early as the second trimester of pregnancy.
The research team, led by Nicola J. Allen at Salk, examined proteins in the brains of mice bred to model Down syndrome. They focused on pleiotrophin because it appears at high levels during critical moments of brain development and plays essential roles in forming synapses, the junctions where nerve cells communicate. In Down syndrome mice, pleiotrophin levels were notably reduced.
Pleiotrophin is primarily produced by astrocytes, star-shaped brain cells that support neurons in multiple ways. The researchers found astrocytes contained about twice as much pleiotrophin as another cell type called oligodendrocyte precursor cells, and roughly six times more than microglia. The protein’s levels peak during the first two weeks after birth in mice, exactly when synapses are forming most rapidly, then decline as the brain matures.
Delivering the Molecule Where It’s Needed
To test whether restoring pleiotrophin would help, the scientists used modified viruses as delivery vehicles. They stripped the viruses of their disease-causing components and loaded them with genetic instructions for making pleiotrophin, then injected these carriers into mice at 60 days old, well past the typical window for brain development.
The results were striking. In the hippocampus, a brain region crucial for memory, neurons in treated Down syndrome mice grew longer, more complex branches and developed more dendritic spines, the tiny protrusions where synapses form. The treatment also increased the number of functional synapses and improved a form of short-term plasticity, the brain’s ability to strengthen connections, which had been impaired in the Down syndrome mice.
“These results suggest we can use astrocytes as vectors to deliver plasticity-inducing molecules to the brain. This could one day allow us to rewire faulty connections and improve brain performance.”
The improvements occurred even though the mice were adults when treated. That’s significant because it means the intervention doesn’t have to happen during the brief, precise developmental windows that would be nearly impossible to time in human pregnancies.
The researchers don’t think pleiotrophin deficiency tells the whole story of Down syndrome. Previous work from Allen’s lab showed that astrocytes in Down syndrome mice don’t just produce less of some beneficial molecules, they also overproduce potentially harmful ones. The complete picture likely involves multiple factors working together.
Brandebura emphasized that the approach could extend beyond Down syndrome. “This idea that astrocytes can deliver molecules to induce brain plasticity has implications for many neurological disorders, including other neurodevelopmental disorders like fragile X syndrome but also maybe even to neurodegenerative disorders like Alzheimer’s disease,” she said. The research showed pleiotrophin levels were also reduced in mouse models of Rett syndrome and fragile X syndrome.
The work remains far from clinical application. The mice, while useful models, don’t perfectly replicate human Down syndrome. The behavioral tests didn’t show improvements, though the anatomical and electrical measurements did. And delivering modified viruses to human brains raises safety questions that will require extensive testing.
Still, the proof of concept matters. If astrocytes can be reprogrammed to deliver the right molecules at the right times, it could provide a new way to address not just Down syndrome but a range of conditions where brain circuits don’t form or function correctly.
Cell Reports: 10.1016/j.celrep.2025.116300
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