Summary

Intensive training in young mice staves off symptoms of a rare neurological disorder that afflicts young girls. The discovery may spark new ideas for treatments in humans.

Training in a water maze activates a set of neurons (red) in the mouse hippocampus. These neurons are critical for the improved performance scientists see after training young Rett mice. Credit: N.P. Achilly et al./Nature 2021

Training babies’ brains and bodies might delay the onset of Rett syndrome, a devastating neurological disorder that affects about 1 in 10,000 girls worldwide.

In experiments with mice that replicate the genetic disorder, scientists discovered that intense behavioral training before symptoms develop staves off both memory loss and motor control decline. Compared to untrained mice, those trained early in life were up to five times better at performing tasks that tested their coordination or their ability to learn, Howard Hughes Medical Institute Investigator Huda Zoghbi and her colleagues report March 24, 2021, in the journal Nature.

Those data, from animals whose symptoms closely mimic the human disease, offers a clear rationale for genetically screening newborns for Rett syndrome, says Zoghbi, a physician and geneticist at Baylor College of Medicine who has been studying the disorder for more than 30 years.

Rett syndrome primarily affects girls, who are typically diagnosed around age three ­– well after symptoms first appear. An earlier diagnosis could offer a window of opportunity for treatment, she says – potentially delaying disease progression in children, or even making them better able to benefit from future therapies. “We are losing precious time,” Zoghbi says. “If we could screen these girls and put them through training, maybe the time we gain prior to overt onset of symptoms will also create more opportunity for other treatments to work.”

A rapid decline

There are no effective treatments for Rett syndrome, and the unrelenting barrage of symptoms is grim. After developing normally for roughly the first one to two years of life, children progressively lose skills they’ve learned. By 18 months, kids may have trouble using their hands. By two years, their ability to balance deteriorates and language skills fade. When symptoms are full-blown, almost every part of the brain is affected. In severe cases, girls cannot talk, feed themselves, or even open their mouths. They can also experience seizures, teeth grinding, and difficulty breathing.

For parents watching their daughters regress, “it’s the most painful thing you can imagine,” Zoghbi says. Her journey with Rett syndrome began in 1983, after meeting two young patients who repetitively wrung their hands, a hallmark of the disorder. Zoghbi was convinced that Rett syndrome had a genetic root. In 1999, her team discovered that mutations in a gene on the X chromosome were to blame. A defective copy of the gene, called MECP2, disables about half the brain’s neurons, so that they function at only about 50-70% of their normal capacity, the team reported in 2011 and 2016.

At first, infants with Rett syndrome (red line) develop like healthy infants (black line), reaching typical developmental milestones such as rolling over, sitting up, and crawling. But after about a year, the babies begin to lose the skills they’ve learned. Behavioral training before Rett symptoms develop (blue dotted line) could potentially delay the disease’s onset, experiments in mice suggest. Credit: Huda Zoghbi

Correcting MECP2 via gene therapy would be an ideal treatment, Zoghbi’s team writes, but delivering the right dose to the right neurons poses a challenge. Too much MECP2 can cause neurological problems, too. Scientists are currently pursuing a gene therapy candidate for Rett syndrome, though clinical trials have not yet begun.

Zoghbi’s team took an alternative approach. What if researchers could somehow prod those sluggish neurons into action? Using electrodes implanted in the brains of “Rett mice,” Zoghbi and her colleagues discovered that stimulating key neurons at the base of the brain activated hippocampal neurons and improved learning and memory, cranking neural activity back up to normal. The team reported the results of this deep brain stimulation in Nature in 2015. “That was really, really exciting,” Zoghbi says. “It gave us the idea that boosting the neurons’ activity could help them.”

Implanting electrodes into the brain isn’t ideal for children, though. For one thing, all brain regions are affected by Rett syndrome. So Zoghbi’s team tried to mimic the effects of deep brain stimulation with something non-invasive – intensive behavioral training.

“We thought it might work,” she says, “because both techniques are doing the same thing – stimulating neurons.”

Training time

The team trained Rett mice in two skills that wither in people with the disorder: coordination and learning ability. Instead of training only mice with symptoms, Zoghbi and colleagues tested an unconventional idea, too: They also trained mice before any symptoms had developed.

One type of training included a “rotarod” apparatus, a rolling log-like treadmill that requires mice to continuously walk to keep their balance. Twice a week, four times per day, researchers placed mice on the device for a five-minute session. Those trained early in life outperformed those trained later, and they stayed on the apparatus roughly five times longer than mice with no training.

“I’m hopeful that we have a path forward to make a difference in the lives of these individuals.”

Huda Zoghbi, Baylor College of Medicine

The team saw something similar in a water maze test, where mice use pictures on the wall to learn where an underwater platform is hidden. Again, mice trained early performed better those trained after symptoms developed, the researchers found. “The results were really quite stunning,” Zoghbi says. “The difference is huge.” Training was task-specific: mice that received memory training did not make improvements in coordination, for example.

In lab experiments, the team traced improved performance to specific sets of neurons responsible for each training task. Under a microscope, those neurons actually looked different than those from late-trained mice, with more branches and connection points to other neurons. That difference suggests that intense early training physically changes the brain, in a way that counters the disease, Zoghbi says.

In fact, continued training of the animals even held off symptoms, her team discovered. These mice were symptom-free for up to four months longer than untrained mice. That’s a hefty chunk of time for the animals, which, like healthy mice, live about two years. Zoghbi thinks a clinical trial in humans is the next big step for this work. She imagines infant training could take many forms, including extra “tummy time” where babies lie on their stomachs to strengthen their core, or focused language training lessons to help the infants gain a few words.

Screening girls at birth could give doctors the heads-up they need to begin such training – and potentially buy these children some time before the disease begins to encroach. The MECP2 genetic test is widely available and covered by insurance, Zoghbi says.

The team’s findings warrant genetic screening of infant girls, agrees HHMI Investigator Nat Heintz, who was not involved in the research. Whether or not the work will translate to humans is still unknown, “but there are many reasons why it might,” he says. And the payoff could be considerable.

Not only could early treatment delay symptoms, “it’s possible that training may have lasting benefits,” says Heintz, a neuroscientist at The Rockefeller University. “I think people are going to find this exciting.”

Even a delay of six months would be “absolutely worthwhile,” Zoghbi adds. “I’m hopeful that we have a path forward to make a difference in the lives of these individuals.”

###

Citation

Nathan P. Achilly, Wei Wang, and Huda Y. Zoghbi. “Presymptomatic training mitigates functional deficits in a mouse model of Rett syndrome.Nature. Published online March 24, 2021. doi: 10.1038/s41586-021-03369-7

Scientist Profiles

For More Information

Meghan Rosen 301-215-8859 rosenm2@hhmi.org