Angelman Syndrome Seizure Susceptibility Probed in UBE3A Mice

For the first time, researchers have characterized the nerve cell size and electrical activity in a key auditory area of the brain using a UBE3A gene mouse model. The findings may explain why those with Angelman syndrome are more susceptible to seizures.

The study, “Enhanced Transmission at the Calyx of Held Synapse in a Mouse Model for Angelman Syndrome,” was published in Frontiers in Cellular Neuroscience. The work was developed at Erasmus University Medical Center Rotterdam in the Netherlands.

Angelman syndrome is associated with a variety of manifestations, including intellectual disability, speech impairment, walking and balancing issues, and seizures.

Previous studies suggest that the Angelman syndrome mouse model is prone to seizures in response to loud noises.

The AS-associated mutation in the UBE3A gene has been linked to cellular and molecular changes within the hippocampus, a region of the brain affected in epilepsy. However, if these neuronal alterations are present in whole organisms or cells remains unclear.

To understand if and how the mutated UBE3A influences the sound-related (auditory) neuronal pathway, researchers performed auditory stimulation at six distinct intervals (40, 80, 160, 320, 640, 1,280 milliseconds) and recorded the neuron-to-neuron signal transmission in anesthetized UBE3A mice. They did so, at the calyx of Held synapse, a specialized communication between two nerve cells with a key role in the auditory system.

The team reported that UBE3A mice had enhanced synaptic transmission and an increased amplitude in the electrical impulses that send signals around the body, compared to healthy mice used as controls. Scientists believe these molecular phenomenons can contribute to the “increased seizure susceptibility in UBE3A mice and AS patients,” despite the existence of other mechanisms that play a role in seizure onset.

In addition, researchers observed longer-than-normal nerve cells within the medial nucleus of the trapezoid body (MNTB) of UBE3A mice. The MNTB is a collection of brainstem neurons that function within the auditory pathway.

AS mice neurons were activated easily during long sound stimulations, and their nerve cells recovered (changed to a resting status) faster than normal after impulse transmission.

These findings “provide in vivo evidence that UBE3A plays a critical role in controlling synaptic transmission and [neuronal] excitability,” the research team concluded.