Researchers Reverse Symptoms in Neurologic Disease Model


It is a parent’s nightmare: a child is born apparently healthy, then
stops meeting developmental milestones at one year old. Her verbal and
motor skills vanish, and irregular breathing, seizures, and a host of
other problems appear. The cause is Rett syndrome—a devastating genetic,
neurologic disorder that typically affects girls, resulting in severe
disability and often accompanied by autistic behavior. Most Rett
patients will live into middle age and require specialized full-time
care. There is no cure, but researchers from Case Western Reserve
University School of Medicine have been working to find ways to restore
brain function and reverse disabilities
associated with Rett syndrome.

In a recent study, researchers identified a specific brain region—the
medial prefrontal cortex—as being particularly important for some of
the respiratory and cognitive abnormalities seen in Rett syndrome. The
study used a Rett mouse model to show activating neurons in this region
can reverse breathing and memory abnormalities in symptomatic animals.

The team studied mice harboring a defect in the gene that causes Rett
syndrome in humans. In the mouse model, they found neurons in the
medial prefrontal cortex are relatively inactive, because they lack
adequate stimulation from other nerve cells. The researchers
hypothesized that low activity levels in these neurons could be causing
Rett symptoms. By using molecular manipulations, the researchers
specifically activated the “sleeping” neurons. The procedure restored
normal breathing in the mice and reversed a specific deficit in
long-term memory.

“‘Waking up’ these neurons, or increasing their electrical activity,
results in a reversal of disease symptoms. With respect to the behaviors
we studied, we can literally switch the animals from the disease state
to the normal state (and back) by waking up (or not) these neurons,”
explained study lead David M. Katz, PhD, professor of neurosciences and
psychiatry at Case Western Reserve University School of Medicine. “Thus,
despite the severity of Rett syndrome, brain circuits in affected
animals are sufficiently intact that, with appropriate manipulation,
their functionality can be rescued and normal behavior restored.” The
results are part of the PhD thesis research of James Howell, a graduate
student in the Katz laboratory.

The findings suggest stimulating neurons in the medial prefrontal
cortex might also be therapeutic for Rett patients. Researchers hope it
could help normalize breathing and improve cognitive function. The same
approach, applied to other brain regions, could potentially lead to
other improvements, such as enhanced motor function.

Such therapies could also benefit other patients. According to the
authors, Rett syndrome is one of the most physically debilitating
disorders on the autism spectrum and is seen as a potential model for
other types of autism. Said Katz, “Whatever we learn about what is wrong
in the Rett brain, and how to treat this disorder, may be of benefit
not only to Rett patients, but others on the spectrum as well.”

Katz is now working to specifically define the subsets of neurons in
the Rett brain that need to be activated to reverse symptoms. “This will
hopefully make it possible to design more precise therapeutic
strategies,” Katz said. His team is also looking at ways to translate
their mouse model findings into potential treatments for Rett patients.

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