Journal
TRANSLATIONAL PSYCHIATRY
Volume 10, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41398-020-0720-2
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Funding
- NIH [R01NS097808]
- Foundation for Angelman Syndrome Therapeutics
- MIND Institute's Intellectual and Developmental Disabilities Resource Center [NIH U54HD079125]
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Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3a(m-/p+) were reduced in the maternal inherited deletion group with no observable change in the Ube3a(m+/p-) paternal transmission cohort. We also discovered Ube3a(m-/p+) exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3a(m-/p+) and a variety of intriguing neuroanatomical phenotypes while Ube3a(m+/p-) did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS.
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