Star-shaped cells make a molecule that can ‘rewire’ the brains of mice with Down syndrome – understanding how could lead to new treatments

Providing a protein that makes connections to star-shaped cells in the brain could reverse changes in neural circuits seen in Down syndrome, according to new research my colleagues and I published in the journal Cell Reports.

Down syndrome is caused by an error in cell division during development. Individuals receive three copies of chromosome 21 instead of the usual two copies, resulting in duplicates of the genes encoded on chromosome 21. This trisomy causes a host of changes in heart and immune function as well as neurodevelopmental disorders.

Changes in the structure of neurons in people with Down syndrome alter the way they connect to each other. A major type of brain cell called astrocytes helps make connections between neurons. These star-shaped cells have many thin arms that extend into the spaces between neurons. They also secrete various proteins essential for the formation of neuronal connections necessary for brain function.

Researchers found that mouse models of several neurodevelopmental disorders, including Down syndrome, had altered levels of astrocyte proteins during development. My colleagues and I hypothesized that these changes might contribute to the changes in neuronal connections seen in Down syndrome. Could restoring proper levels of some of these astrocyte proteins “rewire” the brain?

Identify an astrocyte protein

First, we needed to choose a candidate astrocyte protein to test our hypothesis. A previous study identified a list of altered astrocyte proteins in a mouse model of Down syndrome. We focused on proteins present at lower levels in astrocytes with Down syndrome compared to unaffected astrocytes. We thought there might not be enough of these proteins available to help form neuronal connections.

Among the top 10 proteins we identified was a molecule called pleiotrophin, or Ptn. This protein is known to help guide axons – long extensions that neurons use to send information to each other – to their targets during development. So it made sense that it could also help neurons form the branching arms they use to receive information.

We found that mice unable to produce Ptn had neurons with fewer branching arms, similar to what we observed in mice with Down syndrome. This correlation implies that appropriate levels of Ptn are necessary to affect neuron branching during brain development.

Restoring neurons in Down syndrome

Next, we wanted to know whether administering Ptn to astrocytes changed neuronal connections in Down syndrome mice.

To answer this question, we integrated the Ptn gene into a small virus with its replication genes removed. Called adeno-associated viruses, these tools allow researchers to deliver genetic material to specific targets in the body and are used for applications such as gene therapy. We introduced the Ptn gene into astrocytes throughout the brains of adult Down syndrome mice to evaluate its effects.

We focused on the visual cortex and hippocampus, areas of the brain involved in vision and memory that are both severely affected by Down syndrome. After enhancing the ability of astrocytes to produce Ptn, we found that both regions recovered levels of neuronal branching density similar to those in mice without Down syndrome.

Finally, we wanted to see if we could actually restore electrical activity levels in the hippocampus by increasing astrocyte Ptn levels. Measuring electrical activity can indicate whether neurons are working properly. After delivering the Ptn gene to the astrocytes of Down syndrome mice, we found that the electrical activity of their hippocampus was restored to levels no different from those of non-Down syndrome mice.

Together, our results show that administration of Ptn to mouse astrocytes can reverse changes in neuronal structure and function observed in Down syndrome. Although our results are far from ready for clinical use, additional research could help us understand if and how Ptn could help improve the health of human patients.

Reconnect the brain

More broadly, our results suggest that astrocyte proteins have the potential to rewire the brain in other neurodevelopmental conditions.

Typically, adult brains have low plasticity, meaning they have a reduced ability to form new connections between neurons. This means that it can be difficult to change neural circuits in adults. We hope that further exploration of how astrocyte proteins can modify the adult brain could lead to new treatments for neurodevelopmental disorders like fragile X syndrome or Rett syndrome, or for neurodegenerative diseases like Parkinson’s disease.

This article is republished from The Conversation, an independent, nonprofit news organization that brings you trusted facts and analysis to help you make sense of our complex world. It was written by: Ashley Brandebura, University of Virginia

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Ashley Brandebura receives funding from NIH NINDS and NIA.