Scientists Find Way To Improve Cognitive Abilities Of Mice With Down Syndrome

The team was able to reverse some of the cognitive effects of a mouse model of Down syndrome. unoL/Shutterstock

Scientists at the University of California, San Francisco (UCSF) have managed to correct some of the memory and learning issues associated with Down syndrome. Their study involved mice that had been genetically engineered to develop a mouse equivalent of Down syndrome, rather than people, but the researchers say their findings are still promising.  

Down syndrome is a condition caused by an extra chromosome. Most people have 23 pairs of chromosomes, which carry genetic material, but people with Down syndrome have three copies of chromosome 21, rather than a pair. The extra chromosome results from an error in cell division and can come from either the mother’s egg or father’s sperm.

Down syndrome can lead to physical changes like poor muscle tone as well as cognitive and behavioral issues like delayed speech development and a short attention span. It can also increase the risk of other health conditions like vision problems and heart abnormalities. Nevertheless, thanks to improvements in care and support for people with Down syndrome, many with the condition live long, happy lives.

Scientists have traditionally focused on the genetics of the condition, but the team behind the new study decided to look at protein production instead. They examined protein production in mice engineered to develop most of the chromosomal, developmental, and cognitive abnormalities that affect humans with Down syndrome using a process called polysome profiling.  

Publishing their findings in Science, the team found that the engineered mice experienced a 39 percent drop in protein production in the hippocampus of their brains, a region central to memory formation. They concluded that this is the result of the activation of a circuit called the integrated stress response (ISR) by cells in the hippocampus. 

The team also found that the ISR was activated in brain samples taken from deceased people who had Down syndrome. They even spotted the pattern in the cells of a person with Down syndrome who only carried an extra chromosome in certain cells. The ISR was only activated in the extra-chromosome cells.

“The cell is constantly monitoring its own health,” explained Professor Peter Walter of UCSF in a statement. “When something goes wrong, the cell responds by making less protein, which is usually a sound response to cellular stress. But you need protein synthesis for higher cognitive functions, so when protein synthesis is reduced, you get a pathology of memory formation.”

To see if they could undo this decline in protein production, the researchers blocked an enzyme in the mice known as PKR, which triggers activation of the IRS. Without this enzyme, the ISR was not activated and protein production did not falter, which in turn improved the mice’s cognitive abilities.

Interestingly, three different approaches successfully improved cognition and even boosted physical brain function. These were deleting the PKR gene altogether, giving the mice a drug that quells activity of the PKR enzyme, and using a drug that enhances protein production to counter the effects of the ISR.

It’s important to remember that the research is in its infancy and is based on findings in mice and post-mortem human tissue. Further research will be needed to confirm the results and find out more about the connection between Down syndrome and the ISR.

Nevertheless, the researchers hope that their findings might contribute to the development of potential treatments for Down syndrome in the future.

In a perspective piece accompanying the study, Mark Halliday and Giovanna Mallucci of the University of Cambridge write that the team “provide compelling evidence that Down syndrome (DS), the most common genetic cause of intellectual disability, joins the pantheon of neurological disorders in which dysregulated ISR signaling plays a key role.”

Activation of the IRS has also been linked to Alzheimer’s, traumatic brain injury, and prion disease, the study authors note.

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