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Preclinical Work Shows How One Gene Causes Severe Mental Retardation

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Duke Health News 919-660-1306

Researchers at Duke University Medical Center and the
University of North Carolina have discovered in mice how a
single disrupted gene can cause a form of severe mental
retardation known as Angelman syndrome.

In a study published in the journal Nature Neuroscience,
they found that the gene, UBE3A, is needed so that neurons in
the brain can form and adjust their connections to other
neurons for storing sensory information.

They also made a promising discovery: When the mice were
deprived of sensory stimulation, the brain connections could be
recovered -- a finding that indicates a pharmaceutical or
behavioral treatment might be possible in the future.

The scientists undertook this project because of the
developmental-onset period seen in Angelman syndrome, typically
when children are between one and two years old.

It is during this time in humans that the cortex, the sheet
of convoluted folds at the surface of the brain, undergoes
profound rearrangements driven by sensory experiences -- the
experience of seeing reorganizes the visual cortex, for
example, during the same time period when the deficits are
becoming obvious in Angelman syndrome, part of the autism
spectrum of disorders.

"We wanted to look at an animal model to learn if this
experience-dependent reorganization of the cortex was abnormal
in animals that were missing the gene," said Michael Ehlers,
MD, PhD, a Duke professor of neurobiology and co-senior author
of the study.

"We looked at the visual cortex, because in this
well-studied model, we could precisely control the sensory
stimulus and study the mice in the light or the dark. We
speculated that similar deficits may be happening in areas of
the cortex that are important for language, cognition, and
emotion, all of which are quite abnormal in Angelman syndrome
patients."

The authors found that brains cells in Angelman syndrome
mice lacked the ability to appropriately strengthen or weaken
in the cortex, an area of the brain important for cognitive
abilities. Angelman syndrome is one among a small family of
single gene, autism-related, neurodevelopmental disorders.

Children with the condition appear to respond normally to
stimuli during their first year, but around 12-18 months, they
start missing milestones of cognitive development and language,
typically learning only two to three words over their
lifetime.

"When we have experiences, connections between brain cells
are modified so that we can learn," said Ben Philpot, PhD, a
University of North Carolina professor in Cell and Molecular
Physiology and co-senior author of the study.

"By strengthening and weakening appropriate connections
between brain cells, a process termed synaptic plasticity, we
are able to constantly learn and adapt to an ever-changing
environment."

"It is difficult to study how experiences lead to changes in
the brain in models of mental retardation," said Koji Yashiro,
PhD, a former University of North Carolina graduate student and
lead author of the study.

"Instead of studying a complex learning model, we studied
how connections between brain cells change in visual areas of
mice exposed to light or kept in darkness. This approach
revealed that brain cells in normal mice can modify their
connections in response to changes in visual experiences, while
the brain cells in Angelman syndrome mice could not."

The inability of brain cells to encode information from
experiences in the Angelman syndrome model suggested that this
is the basis for the profound learning difficulties in these
patients.

The scientists didn't expect to find that the plasticity of
the cellular connections could be restored in visual areas of
the brain after brief periods of visual deprivation.

"By showing that brain plasticity can be restored in
Angelman syndrome model mice, our findings suggest that brain
cells in Angelman syndrome patients maintain a latent ability
to express plasticity. We are now collaborating to find a way
to tap into this latent plasticity, as this could offer a
treatment, or even a cure, for Angelman syndrome," Philpot
said.

Ehlers, who is also a Howard Hughes Medical Investigator,
said that perhaps some of these developmental brain disorders
are a form of social and cognitive blindness. In a condition
known as amblyopia, or cortical blindness, the eye can function
normally, but past a critical period, the brain cannot process
the sensory input correctly.

"We think that children with Angelman syndrome may have a
condition in which sensory experience dampens down plasticity
and affects learning," Ehlers said. "One important aspect of
our findings is that sensory manipulations recovered
plasticity, suggesting that the underlying substrates for
plasticity are intact in mice. If the same thing holds true for
the human disease, there may be a chance to improve brain
function."

Other authors included Kathryn Condon, Duke Department of
Neurobiology; Thorfinn Riday, Adam Roberts, Danilo Bernardo,
and Rohit Prakash of the Curriculum in Neurobiology,
Neuroscience Center, Department of Cell and Molecular
Physiology, and the Neurodevelopmental Disorders Research
Center at the University of North Carolina, Chapel Hill; and
Richard Weinberg, Department of Cell and Developmental Biology,
University of North Carolina. This work was supported by grants
from the National Institutes of Health, the Howard Hughes
Medical Institute, the Angelman Syndrome Foundation, and the
Simons Foundation.

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