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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.