Loss of Protein Underlying Angelman Disrupts Vision-Related Neurons, Mouse Study Finds

Loss of the protein that contributes to Angelman syndrome led to a decrease in the ability of vision-related nerve cells in the brain to process visual information in a mouse model of the disease, a study showed.

The study, “UBE3A loss increases excitability and blunts orientation tuning 2 in the visual cortex of Angelman syndrome model mice,“ was published in the Journal of Neurophysiology.

Angelman syndrome is a neurodevelopmental disorder caused by lack or malfunction of the UBE3A gene. This gene provides instructions for making an enzyme called ubiquitin protein ligase E3A, which adds small molecules called ubiquitin chains to proteins, signaling them for degradation.

In specific regions of the brain, only the maternal UBE3A gene is active, and the paternal gene is turned off and not expressed.

However, when the maternal UBE3A gene is dysfunctional, as is the case in Angelman syndrome, brain cells cannot produce a functional UBE3A protein, leading to a number of serious neurodevelopmental symptoms.

To explore the consequences of UBE3A loss in the brain, researchers used very small electrodes capable of recording electrical impulses in specific neurons.

They then compared the brains of Angelman mice with healthy mice used as controls, in particular the animals’ neuronal response in the visual cortex — a brain area crucial for processing visual stimuli coming from the eyes, including spatial orientation, shape, contrast, and color.

In the Angelman mouse model, visual neurons had abnormal cellular properties: They were over-excitable and could not properly perceive spatial orientation. Contrast sensitivity in these neurons however, remained unchanged.

Restoring a functional UBE3A enzyme in specific neurons of the visual cortex — GABAergic inhibitory neurons — restored neuron excitability to normal and partially reversed the defects in orientation tuning.

“Together these studies point to a critical role for UBE3A in GABAergic neurons in the pathogenesis of AS, and suggest that reinstatement of UBE3A in GABAergic neurons may have a wide range of therapeutic benefits,” the researchers concluded.