Lost Gene Responsible for Angelman Impairs Visual Responses, but Not Light Perception
The loss of the gene responsible for Angelman syndrome impairs the responses of nerve cells to certain visual stimuli but not their ability to perceive changes in luminance, a mouse study suggests.
Importantly, some of these impairments can be corrected by expressing the missing gene in a specific population of nerve cells.
The study, “UBE3A loss increases excitability and blunts orientation tuning in the visual cortex of Angelman syndrome model mice,” was published in the Journal of Neurophysiology.
Angelman syndrome is caused by the loss of the maternal copy of the UBE3A gene. Currently, scientists use a mouse model of the disease in which the same maternal copy is lost, thereby simulating the major features observed in Angelman patients such as ataxia, seizures, and cognitive disabilities.
Previous studies have shown these animals develop neuronal abnormalities in the part of the brain that is involved in vision, known as the visual cortex.
The visual cortex is responsible for performing several actions, of which two are widely studied: orientation tuning and contrast sensitivity. The first is described as the response of a nerve cell depending on the orientation (angle) of a visual stimulus, while the latter is the ability to perceive slight changes in luminance between regions that are not separated by definite borders.
Researchers used an Angelman mouse model that lacks UBE3A in nerve cells but can be genetically modified to conditionally express the gene in a specific type of nerve cells, called GABAergic neurons. These are known as the prime source of inhibition in the adult brain.
Results revealed that UBE3A loss does not affect the contrast response by visual cortex nerve cells but rather results in weaker orientation tuning.
Reinstating UBE3A specifically in GABAergic neurons resulted in an intermediate effect on orientation tuning, suggesting a role for UBE3A in these inhibitory neurons and orientation tuning.
Researchers also measured oscillations in brain activity — through a fixed range (or spectrum) of wave frequency bands — in the presence and absence of visual stimulation. This is of particular relevance, since Angelman patients present brain activity abnormalities, as measured by electroencephalography (EEG), particularly in the so-called delta band.
Visual stimulation in the animals greatly increased spectral power in another frequency band, called gamma band. However, no differences were observed in spectral power between mice lacking the UBE3A gene and normal controls, either during baseline conditions or with visual stimulation.
“Our negative results with respect to contrast sensitivity suggest that the function of visual circuits remains largely intact in AS model mice at the retinal and thalamic stages,” researchers wrote.
“Overall, this work demonstrates that maternal Ube3a loss disrupts cortex-dependent computations,” they added.
Reinstating the UBE3A gene in GABAergic neurons “may have a wide range of therapeutic benefits,” the authors concluded.
