Scientists rewired Down syndrome brain circuits by restoring a missing molecule

The work was done in laboratory mice, not in people, so it is not close to becoming a treatment. Even so, the researchers found that giving pleiotrophin improved brain function in adult mice after the brain had already finished forming. This raises the possibility of an advantage over earlier strategies aimed at strengthening Down syndrome related brain circuits, which would have required action during very narrow windows in pregnancy.

"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, PhD, who was part of the research team while at the Salk Institute for Biological Studies and is now part of the University of Virginia School of Medicine. "This is still far off from use in humans, but it gives us hope that secreted molecules can be delivered with effective gene therapies or potentially protein infusions to improve quality of life in Down syndrome."

Understanding Down syndrome and its health impacts

Down syndrome affects about 1 in 640 babies born each year in the United States, according to the federal Centers for Disease Control and Prevention. It results from an error in cell division during development and can be associated with developmental delays, hyperactivity, a shorter lifespan, and a higher risk of health issues that can include heart defects, thyroid problems, and hearing or vision difficulties.

Salk scientists led by Nicola J. Allen, PhD, set out to learn more about what drives Down syndrome by examining proteins inside brain cells in mouse models of the condition. They focused on pleiotrophin because it normally appears at very high levels at key stages of brain development and plays important roles in building synapses, the connections between nerve cells, and in shaping axons and dendrites, which help neurons send and receive signals. The researchers also noted that pleiotrophin levels are reduced in Down syndrome.

To test whether restoring pleiotrophin could improve brain function, the team used engineered viruses called viral vectors to deliver it to the right place. Viruses are often associated with illnesses like the flu, but researchers can modify them so they do not cause disease and instead carry helpful material. In this case, the virus was stripped of harmful components and loaded with beneficial cargo -- pleiotrophin -- so it could deliver the molecule directly into cells.

Astrocytes, synapses, and brain plasticity

The scientists reported that supplying pleiotrophin to astrocytes, a major type of brain cell, produced substantial effects. Among the changes, the number of synapses increased in the hippocampus, a region involved in learning and memory. The team also saw an increase in brain "plasticity" -- the ability to create or adjust connections that support learning and memory.

"These results suggest we can use astrocytes as vectors to deliver plasticity-inducing molecules to the brain," Allen said. "This could one day allow us to rewire faulty connections and improve brain performance."

Broader implications and next steps

The researchers emphasize that pleiotrophin is unlikely to be the only factor behind circuit problems in Down syndrome. They say more work is needed to understand the many contributors involved. Still, they argue that the results show the approach itself can work, and that it might eventually help beyond Down syndrome, including in other neurological diseases.

"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," Brandebura said. "If we can figure out how to 'reprogram' disordered astrocytes to deliver synaptogenic molecules, we can have some greatly beneficial impact on many different disease states."

After finishing her postdoctoral training at Salk, Brandebura plans to continue this line of research at UVA Health. There, she is part of the UVA Brain Institute, the Department of Neuroscience and the Center for Brain Immunology and Glia (BIG Center).

Findings published and funding

The results were published in the journal Cell Reports. The article is opening access, meaning it is free to read. The research team included Brandebura, Adrien Paumier, Quinn N. Asbell, Tao Tao, Mariel Kristine B. Micael, Sherlyn Sanchez and Allen. The scientists report no financial interest in the work.

Support came from the Chan Zuckerberg Initiative and the National Institutes of Health's National Institute of Neurological Disorders and Stroke, grant F32NS117776.