According to new research that my colleagues and I published in the journal Cell Reports, administering a protein that facilitates the connection between neurons to the stellate cells of the brain could reverse the alterations in neuronal circuits observed in Down syndrome.
Down syndrome is due to an error in cell division during development. People with this condition receive three copies of chromosome 21 instead of the usual two, resulting in the duplication of the genes encoded on that chromosome. This trisomy leads to multiple alterations in cardiac and immune function, as well as neurodevelopmental disorders.
Alterations in the structure of neurons in people with Down syndrome modify the way they connect with each other. An important type of brain cell, called an astrocyte, contributes to the formation of connections between neurons. These stellate cells have numerous thin processes that extend into the interneuronal spaces. In addition, they secrete various proteins essential for the formation of neuronal connections necessary for proper brain function.
The researchers found that mouse models of several neurodevelopmental disorders, including Down syndrome, exhibit altered levels of astrocyte proteins during development. My colleagues and I hypothesized that these changes could contribute to the alterations in neural connections seen in Down syndrome. Could restoring proper levels of some of these astrocyte proteins “rewire” the brain?
Identification of an astrocyte protein
First, we needed to select a candidate astrocyte protein to test our hypothesis. A previous study had identified a list of altered astrocyte proteins in a mouse model of Down syndrome. We focused on proteins present at lower levels in astrocytes from mice with Down syndrome compared to astrocytes from mice without this condition. We thought there might not be enough proteins available to help form neural 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 branches they use to receive information.
We discovered that mice unable to produce Ptn had neurons with less branching, similar to what was observed in mice with Down syndrome. This correlation implies that adequate levels of Ptn are necessary to influence neuronal branching during brain development.
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Restoration of neurons in Down syndrome
Next, we wanted to know if the administration of Ptn to astrocytes modifies neuronal connections in mice with Down syndrome.
To answer this question, we introduced the Ptn gene into a small virus that had its replication genes removed. These viruses, called adeno-associated viruses, allow researchers to deliver genetic material to specific targets in the organism and are used in applications such as gene therapy. We delivered the Ptn gene to astrocytes throughout the brain of adult mice with Down syndrome to evaluate its effects.
We focus on the visual cortex and the hippocampus, brain areas involved in vision and memory, both severely affected in Down syndrome. After enhancing the ability of astrocytes to produce Ptn, we observed that both regions recovered levels of neuronal branching density similar to those of mice without Down syndrome.
Finally, we wanted to see if we could restore levels of electrical activity in the hippocampus by increasing Ptn levels in astrocytes. Measuring electrical activity can indicate whether neurons are working properly. After introducing the Ptn gene into the astrocytes of mice with Down syndrome, we observed that the electrical activity of their hippocampus was restored to levels similar to those of mice without Down syndrome.
Taken together, our findings demonstrate that introduction of Ptn into mouse astrocytes can reverse the alterations in neuronal structure and function observed in Down syndrome. While our findings are not yet ready for clinical use, further research could help us understand if and how Ptn could contribute to improving the health of human patients.
Brain Rewiring
More broadly, our findings suggest that astrocyte proteins have the potential to rewire the brain in other neurodevelopmental conditions.
The adult brain generally has low plasticity, meaning it has a reduced ability to form new connections between neurons. This implies that it may be difficult to modify neural circuits in adults. We hope that further research into how astrocyte proteins can alter the adult brain will lead to new treatments for neurodevelopmental disorders such as fragile X syndrome or Rett syndrome, or for neurodegenerative diseases such as Parkinson’s disease.
*Ashley Brandebura is an associate professor of neuroscience at the University of Virginia.
This text was originally published in The Conversation
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