According to new research that my colleagues and I published in the journal Cell Reports, delivering a protein that strengthens communication to stellate cells in the brain can reverse the changes in neural circuits seen in Down syndrome.
Down syndrome is caused by an error in cell division during development. Individuals receive three copies of chromosome 21 instead of the normal two copies, resulting in duplicate genes encoded on chromosome 21. This trisomy causes a number of changes in cardiac and immune function, as well as neurodevelopmental disorders.
Changes in the structure of neurons in people with Down syndrome change how they communicate with each other. One of the main types of brain cells, called astrocytes, helps form connections between neurons. These star-shaped cells have many thin arms that extend into the spaces between neurons. They also secrete various proteins that are vital for forming the proper nerve connections needed for brain function.
The researchers found that mouse models of several neurodevelopmental disorders, including Down syndrome, had altered protein levels in astrocytes during development. My colleagues and I hypothesized that these changes may contribute to the changes in neural connections seen in Down syndrome. Can restoring the proper levels of some of these astrocyte proteins “rewire” the brain?
Determination of astrocyte protein
First, we had to select a candidate astrocyte protein to test our hypothesis. A previous study identified a list of astrocyte proteins that were altered in a mouse model of Down syndrome. We focused on proteins with lower levels in Down syndrome astrocytes compared to astrocytes without the condition. We hypothesized that these proteins might not be sufficient to form neural connections.
Among the top 10 proteins we identified was a molecule called pleiotropin, or Ptn. This protein is known to help direct axons, the 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 saw in mice with Down syndrome. This correlation implies that adequate levels of Ptn are necessary to influence neuronal branching during brain development.
Neuronal regeneration in Down syndrome
Next, we wanted to know whether delivery of Ptn to astrocytes alters neural connections in mice with Down syndrome.
To answer this question, we packaged the Ptn gene into a small virus from which its replication genes had been removed. These tools, called adeno-associated viruses, 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 brain of adult mice with Down syndrome to evaluate its effects.
We focused on the visual cortex and hippocampus, areas of the brain associated with vision and memory, both of which are severely affected in Down syndrome. After increasing the ability of astrocytes to produce Ptn, we found that both regions regained nerve branching density similar to mice without Down syndrome.
Finally, we wanted to see if we could actually restore the level of electrical activity in the hippocampus by increasing astrocyte Ptn levels. Measuring electrical activity can show whether neurons are working properly. By introducing the Ptn gene into the astrocytes of mice with Down syndrome, we found that their hippocampal electrical activity was restored to a level indistinguishable from mice without Down syndrome.
Together, our findings suggest that delivery of Ptn to murine astrocytes can reverse the changes in neuronal structure and function observed in Down syndrome. Although our findings are far from being ready for use in the clinic, more research could help us understand if and how Ptn could help improve patient health.
Brain rewiring
More broadly, our findings suggest that astrocyte proteins may alter the brain in other neurodevelopmental conditions.
In general, the adult brain has little plasticity, meaning it has a reduced ability to form new connections between neurons. This means that it can be difficult for adults to change neural circuits. We hope that further investigation of how astrocyte proteins can alter the adult brain could lead to new treatments for neurodevelopmental disorders such as Fragile X syndrome or Rett syndrome, or neurodegenerative diseases such as Parkinson’s disease.
This article is republished from The Conversation, a not-for-profit independent news organization that provides facts and sound analysis to help make sense of our complex world. Posted by Ashley Brandebura, University of Virginia
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Ashley Brandebura receives funding from NIH NINDS and NIA.