UBE3A protein lacking in patients needed early for brain circuitry

Mouse study spots crucial life window when protein promotes development

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The UBE3A protein is needed shortly after birth for the proper development of the dorsomedial striatum, part of a brain region called the basal ganglia, a mouse study suggests.

Findings shed new light on the neurological disruptions that give rise to Angelman syndrome and its symptoms, a disease caused by mutations that result in a lack of the UBE3A protein. A better understanding of how and when these neurological abnormalities appear will be crucial for designing therapies, its researchers said.

The study, “UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation,” was published in the journal JCI Insight.

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Within the brain, nerve cells (neurons) form branching connections with each other, giving rise to a complex network of neurological circuits. These nerve circuits form in early development and have a particular window of time in which they normally mature. After this critical window, the structure of the circuit becomes harder to change.

In neurodevelopmental disorders like Angelman, abnormalities in brain circuitry are thought to be the main driver of behavioral and cognitive disease symptoms. However, how these circuits are disrupted in Angelman is poorly understood. Scientists in the Netherlands conducted a study in a mouse model to learn more.

“It is important to identify both the neuronal circuits that underlie the clinical [symptoms] and their critical window for therapeutic intervention,” the researchers wrote.

They specifically focused on the dorsomedial striatum (DMS), part of a larger brain structure called the basal ganglia that is involved in the integration and selection of voluntary behavior. Specifically, the DSM is involved in coordinating goal-directed actions.

“The DMS is involved in the early phases of motor learning … and motor learning deficits, which are clearly present both in patients and in [Angelman syndrome] mouse models,” the researchers wrote.

Scientists began by analyzing brains from adult mice, and found that mice in an Angelman model lacking UBE3A showed abnormalities in neuron activity in the DMS. Compared with wild-type (healthy) mice, neurons in the Angelman mice showed deficits in their ability to send chemical signals to other neurons.

The team then analyzed brains of mice at several points during the first month after birth, which is when the DMS normally matures in mice.

In Angelman model mice, DMS development appeared normal for the first two weeks after birth. But abnormalities were detectable by the third week of life, becoming more pronounced at later time points. Further analyses suggested that DMS neurons in Angelman mice were maturing more slowly during the third week of life, a point of critical development for the DMS.

More normal brain activity in young mice with ‘turned on’ protein

The scientists next conducted experiments using a genetically engineered Angelman mouse model, one in which expression of the UBE3A protein can be turned on by giving tamoxifen, a breast cancer medication, to the mice.

In this model, the researchers showed that neuronal activity in the DMS could be normalized if UBE3A protein was turned on at 21 days after birth. However, if the protein was not expressed until about two months after birth, changes in nerve activity persisted even with normal levels of UBE3A.

Angelman mice normally show deficits on the lever press test, a measure of learning ability. Mice where UBE3A was expressed starting on the third week after birth showed improvements in this test, though they did not perform as well as wild-type mice. By contrast, when UBE3A was not turned on until two months after birth, no improvement on this learning test was seen.

Mice with normal UBE3A expression during early brain development, who then were treated to stop expressing the protein, also showed no significant abnormalities on the lever press test.

Overall, the findings highlight an important role of UBE3A during a critical period of brain maturation. The time around three weeks after birth in mice is “the critical therapeutic window in which treatment has to be initiated to prevent [DMS] dysfunction,” the researchers noted.

These scientists stressed a need for further work to understand how these mouse results might translate to people, and they also emphasized the need for more work to understand the effects of Angelman syndrome in specific areas of the brain.