(Image caption: In the neuron, a protective
covering called myelin (grey) insulates the axon and increases the speed
of electrical communication along the length of the neuron. Credit: Opus Design)

Neuroscientists reverse some behavioral symptoms of Williams Syndrome

Williams Syndrome, a rare neurodevelopmental disorder that affects
about 1 in 10,000 babies born in the United States, produces a range of
symptoms including cognitive impairments, cardiovascular problems, and
extreme friendliness, or hypersociability.

In a study of mice, MIT neuroscientists have garnered new insight
into the molecular mechanisms that underlie this hypersociability. They
found that loss of one of the genes linked to Williams Syndrome leads to
a thinning of the fatty layer that insulates neurons and helps them
conduct electrical signals in the brain.

The researchers also showed that they could reverse the symptoms by
boosting production of this coating, known as myelin. This is
significant, because while Williams Syndrome is rare, many other
neurodevelopmental disorders and neurological conditions have been
linked to myelination deficits, says Guoping Feng, the James W. and
Patricia Poitras Professor of Neuroscience and a member of MIT’s
McGovern Institute for Brain Research.

“The importance is not only for Williams Syndrome,” says Feng, who is
one of the senior authors of the study. “In other neurodevelopmental
disorders, especially in some of the autism spectrum disorders, this
could be potentially a new direction to look into, not only the
pathology but also potential treatments.”

Zhigang He, a professor of neurology and ophthalmology at Harvard
Medical School, is also a senior author of the paper, which appeared in
Nature Neuroscience. Former MIT postdoc
Boaz Barak, currently a principal investigator at Tel Aviv University in
Israel, is the lead author and a senior author of the paper.

Impaired myelination

Williams Syndrome, which is caused by the loss of one of the two
copies of a segment of chromosome 7, can produce learning impairments,
especially for tasks that require visual and motor skills, such as
solving a jigsaw puzzle. Some people with the disorder also exhibit poor
concentration and hyperactivity, and they are more likely to experience

In this study, the researchers decided to focus on one of the 25
genes in that segment, known as Gtf2i. Based on studies of patients with
a smaller subset of the genes deleted, scientists have linked the Gtf2i
gene to the hypersociability seen in Williams Syndrome.

Working with a mouse model, the researchers devised a way to knock
out the gene specifically from excitatory neurons in the forebrain,
which includes the cortex, the hippocampus, and the amygdala (a region
important for processing emotions). They found that these mice did show
increased levels of social behavior, measured by how much time they
spent interacting with other mice. The mice also showed deficits in fine
motor skills and increased nonsocial related anxiety, which are also
symptoms of Williams Syndrome.

Next, the researchers sequenced the messenger RNA from the cortex of
the mice to see which genes were affected by loss of Gtf2i. Gtf2i
encodes a transcription factor, so it controls the expression of many
other genes. The researchers found that about 70 percent of the genes
with significantly reduced expression levels were involved in the
process of myelination.

“Myelin is the insulation layer that wraps the axons that extend from
the cell bodies of neurons,” Barak says. “When they don’t have the
right properties, it will lead to faster or slower electrical signal
transduction, which affects the synchronicity of brain activity.”

Further studies revealed that the mice had only about half the normal
number of mature oligodendrocytes — the brain cells that produce
myelin. However, the number of oligodendrocyte precursor cells was
normal, so the researchers suspect that the maturation and
differentiation processes of these cells are somehow impaired when Gtf2i
is missing in the neurons.

This was surprising because Gtf2i was not knocked out in
oligodendrocytes or their precursors. Thus, knocking out the gene in
neurons may somehow influence the maturation process of
oligodendrocytes, the researchers suggest. It is still unknown how this
interaction might work.

“That’s a question we are interested in, but we don’t know whether
it’s a secreted factor, or another kind of signal or activity,” Feng

In addition, the researchers found that the myelin surrounding axons
of the forebrain was significantly thinner than in normal mice.
Furthermore, electrical signals were smaller, and took more time to
cross the brain in mice with Gtf2i missing.

The study is an example of pioneering research into the contribution
of glial cells, which include oligodendrocytes, to neuropsychiatric
disorders, says Doug Fields, chief of the nervous system development and
plasticity section of the Eunice Kennedy Shriver National Institute of
Child Health and Human Development.

“Traditionally myelin was only considered in the context of diseases
that destroy myelin, such as multiple sclerosis, which prevents
transmission of neural impulses. More recently it has become apparent
that more subtle defects in myelin can impair neural circuit function,
by causing delays in communication between neurons,” says Fields, who
was not involved in the research.

Symptom reversal

It remains to be discovered precisely how this reduction in
myelination leads to hypersociability. The researchers suspect that the
lack of myelin affects brain circuits that normally inhibit social
behaviors, making the mice more eager to interact with others.  

“That’s probably the explanation, but exactly which circuits and how does it work, we still don’t know,” Feng says.

The researchers also found that they could reverse the symptoms by
treating the mice with drugs that improve myelination. One of these
drugs, an FDA-approved antihistamine called clemastine fumarate, is now
in clinical trials to treat multiple sclerosis, which affects
myelination of neurons in the brain and spinal cord. The researchers
believe it would be worthwhile to test these drugs in Williams Syndrome
patients because they found thinner myelin and reduced numbers of mature
oligodendrocytes in brain samples from human subjects who had Williams
Syndrome, compared to typical human brain samples.

“Mice are not humans, but the pathology is similar in this case,
which means this could be translatable,” Feng says. “It could be that in
these patients, if you improve their myelination early on, it could at
least improve some of the conditions. That’s our hope.”

Such drugs would likely help mainly the social and fine-motor issues
caused by Williams Syndrome, not the symptoms that are produced by
deletion of other genes, the researchers say. They may also help treat
other disorders, such as autism spectrum disorders, in which myelination
is impaired in some cases, Feng says.

“We think this can be expanded into autism and other
neurodevelopmental disorders. For these conditions, improved myelination
may be a major factor in treatment,” he says. “We are now checking
other animal models of neurodevelopmental disorders to see whether they
have myelination defects, and whether improved myelination can improve
some of the pathology of the defects.”

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