Behavioral deficits in an Angelman syndrome model: Effects of genetic background and age

Abstract

Angelman syndrome (AS) is a severe neurodevelopmental disorder associated with disruption of maternally inherited UBE3A (ubiquitin protein ligase E3A) expression. At the present time, there is no effective treatment for AS. Mouse lines with loss of maternal Ube3a (Ube3am–/p+) recapitulate multiple aspects of the clinical AS profile, including impaired motor coordination, learning deficits, and seizures. Thus, these genetic mouse models could serve as behavioral screens for preclinical efficacy testing, a critical component of drug discovery for AS intervention. However, the severity and consistency of abnormal phenotypes reported in Ube3am–/p+ mice can vary, dependent upon age and background strain, which is problematic for the detection of beneficial drug effects. As part of an ongoing AS drug discovery initiative, we characterized Ube3am–/p+ mice on either a 129S7/SvEvBrd-Hprtb-m2 (129) or C57BL/6J (B6) background across a range of functional domains and ages to identify reproducible and sufficiently large phenotypes suitable for screening therapeutic compounds. The results from the study showed that Ube3am–/p+ mice have significant deficits in acquisition and reversal learning in the Morris water maze. The findings also demonstrated that Ube3am–/p+ mice exhibit motor impairment in a rotarod task, hypoactivity, reduced rearing and marble-burying, and deficient fear conditioning. Overall, these profiles of abnormal phenotypes can provide behavioral targets for evaluating effects of novel therapeutic strategies relevant to AS.

Angelman Syndrome

“…Generally, Ube3a m-/p+ mice show decreased freezing in contextual fear conditioning and no deficit in cued fear conditioning, although the opposite has also been reported [35,36,38]. Depending on the strain and reporting laboratory, Ube3a m-/p+ mice may show a deficit in water-maze acquisition, testing, or reversal training [35,36,38,42]. Anxiety phenotypes are reported, as shown by dark preferences in light-dark tests and lack of novel object preference, as well as preference for edges and increased freezing in open field-testing [38,43].…”

“…Differences in gait analysis, clasping, pole test, and tape removal are less consistently reported [40]. Hypoactivity has been shown in the Ube3a m-/p+ animals both in an open field type of environment, reflected in slower speed and less distance travelled, and in water-maze testing, where slower swim speed is observed [38]. Generally, Ube3a m-/p+ mice show decreased freezing in contextual fear conditioning and no deficit in cued fear conditioning, although the opposite has also been reported [35,36,38].…”

“…Hypoactivity has been shown in the Ube3a m-/p+ animals both in an open field type of environment, reflected in slower speed and less distance travelled, and in water-maze testing, where slower swim speed is observed [38]. Generally, Ube3a m-/p+ mice show decreased freezing in contextual fear conditioning and no deficit in cued fear conditioning, although the opposite has also been reported [35,36,38]. Depending on the strain and reporting laboratory, Ube3a m-/p+ mice may show a deficit in water-maze acquisition, testing, or reversal training [35,36,38,42].…”

“…Maternal (and not paternal) deletion of Ube3a (referred to as Ube3a m-/p+ ) mediates the behavioral phenotypes. For the mouse models of AS caused by Ube3a maternal deletions, there is some phenotypic inconsistency, after accounting for genotype and background strain [38]. Motor deficits on rotarod and beam balance tests have been seen consistently [25,35,36,38,39].…”

“…Depending on the strain and reporting laboratory, Ube3a m-/p+ mice may show a deficit in water-maze acquisition, testing, or reversal training [35,36,38,42]. Anxiety phenotypes are reported, as shown by dark preferences in light-dark tests and lack of novel object preference, as well as preference for edges and increased freezing in open field-testing [38,43]. Mice with AS bury fewer marbles than their wild-type controls [38].…”