Early, intensive training in motor and memory skills before symptoms develop may delay disease progression and help children with Rett syndrome retain specific milestones, a study in mice suggests.
Observed benefits were not evident when training was given to symptomatic animals, its researchers wrote, supporting “genetic screening of newborns for Rett syndrome, as presymptomatic intervention might mitigate symptoms or delay their onset.”
The study, “Presymptomatic training mitigates functional deficits in a mouse model of Rett syndrome,” was published in the journal Nature.
This study was led by Huda Zoghbi, MD, a geneticist and professor at Baylor College of Medicine. Zoghbi has worked on Rett syndrome, a progressive neurological disorder that primarily affects girls, for decades — her lab was the first to identify mutations in the gene MECP2 as a genetic cause of the disease in 1999.
“Years ago, I decided to study Rett syndrome because it struck me as a neurological condition like no other I had seen before,” Zoghbi said in a press release.
“What I saw with Rett syndrome was that girls … born looking like any other healthy baby” developed as expected until 1 or 2 years old, then “gradually lost the skills they had developed — they began to have trouble walking and with balance, slowly lost their ability to communicate and started to wring their hands constantly,” Zoghbi said.
“The condition then stabilizes,” she added, “but the girls remain disabled for the rest of their lives.”
Prior work by Zoghbi and colleagues showed that deep brain stimulation (DBS) — where an electrical current is used to stimulate parts of the brain — could improve memory and learning in a mouse model of Rett syndrome. But individual symptoms respond to different types of DBS treatment, and its use in a clinical setting is not feasible.
“We therefore wondered whether there might be ways of mimicking the effects of consistent stimulation without the invasiveness of DBS,” the researchers wrote.
Behavioral training was one approach considered. The researcher team thought such training might provide similar benefits to DBS, “because both techniques are doing the same thing — stimulating neurons,” Zoghbi said in a separate press release. (Neurons are key cells of the brain and nervous system that, among other duties, transmit electrical signals.)
A series of experiments in female mice engineered to mimic manifestations of Rett used standard tasks to measure coordination (rotarod test) and memory (Morris water maze).
Some of these mice were separated into two groups and given regular training in these tasks. One group started training before symptoms showed, and the other group started training weeks after symptoms were evident.
Mice trained presymptomatically — motor symptoms first show in this model at around 12 weeks old — performed significantly better on these tests than did either untrained diseased mice or mice who started training after showing symptoms, the researchers reported.
With the rotarod test, for example, presymptomatic mice started training (four times a day, biweekly) at age 8 weeks, and continued beyond age 24 weeks. The symptomatic group began training at age 22 weeks.
“At 32 weeks of age, the performance of early-trained Rett mice was comparable to that of [training] naive 12-week-old Rett mice,” the researchers wrote, while symptomatic mice showed no ability to retain skills learned, even if training “was begun earlier, at 16 weeks.”
Improvements were specific to the type of training the mice underwent, however. For example, mice that underwent memory training showed no improvement in coordination.
“The mice only improved in what they had trained for,” Zoghbi said.
Collectively, these findings suggest that early training could ease symptoms that arise later in life for Rett children. But early diagnoses will be key to implementing such early training, the researchers said.
“Our findings lead us to propose that newborn genetic testing for Rett syndrome, followed by prompt intensive training in the tasks that will be affected, could help the girls retain specific milestones and delay the onset of symptoms,” Zoghbi said.
Further experiments looked into the neurological underpinnings of training. Through a series of labeling experiments, researchers identified “task-specific” neurons that fired (were activated) during a specific task, but did not fire during an unrelated task.
They then used genetic engineering technologies to introduce specialized protein receptors to task-specific nerve cells in mice. The goal of this work was to engineered mice so that these task-specific neurons could be “turned on” or “turned off” with specific chemicals.
They found that preventing the reactivation of these neurons affected benefits seen with early training. In other experiments, the mice underwent a single training session. Then, instead of giving these mice additional sessions, the researchers just activated their task-specific neurons.
Mice with these chemically activated neurons also performed significantly better than other mice when assessed on the task. In essence, they gained the benefits of training through the activation of specific neurons.
“The discovery that presymptomatic training leads to behavioural improvements in a physiologically relevant model of Rett syndrome has practical implications for individuals with the disorder,” the researchers concluded. “Above all, it suggests that early behavioural training could improve functionality and delay the onset of specific symptoms.”
It also supports “newborn genetic testing for Rett syndrome, followed by prompt intensive training in the behavioural domains that will be affected (for example, gait/balance, manual dexterity and communication),” they added.
Such early diagnosis, coupled with intensive training “may also augment the efficacy of future therapies.”
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