Behavioral Phenotypes in Mouse Models of Angelman Syndrome

Background: The mouse model for Angelman syndrome was developed over 15 years ago, but represents one of the most useful mouse models for a human cognitive disorder. The AS mouse shows strong phenotypes in the areas of motor coordination, learning and memory, seizure propensity and hippocampal synaptic function.

Objectives: To determine if the strongest phenotypes of the AS mouse model can be reversed in the adult mouse.

Methods: We used Ube3a maternal deficient mice on a background strain of C57BL/6 and 129Svev.  The C57BL/6 strain was used for testing learning and memory. The 129Svev strain was used to for testing seizure propensity, duration and EEG abnormalities.

Results: We find that these specific phenotypes can be rescued with multiple strategies. Protein replacement with Adeno-Associated virus, dietary supplementation and pharmacological intervention have all shown promise as potential therapeutic avenues.

Conclusions: There are multiple molecular sites for therapeutic intervention. It is likely that the AS phenotype can be overcome by multiple strategies due to the global effect of Ube3a deficiency and not a specific singular molecular problem.  These associations have implications on future clinical trials and how the AS mouse may be used for further preclinical research.