Translation in Fast Forward: Cross Species Research on Deletions and Duplications of Chromosome 15q11.2-q13

Background:

Mutations in chromosomal region 15q11.2-q13 result in at least three neurodevelopmental disorders including Angelman, Prader-Willi and Dup15q Syndromes, all associated with autism spectrum disorders (ASD). Angelman Syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired receptive and expressive communication skills, ataxia, motor and balance deficits, poor attention, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is loss of expression of UBE3A (ubiquitin-protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Duplications or triplications of chromosome 15q11.2-q13 (Dup15q) are one of the most common and penetrant genomic rearrangements observed in ASD, accounting for up to ~3% of cases. New advances in mouse and rat models have allowed for the development and utilization of clinically-relevant behavioral assays to measure sophisticated outcomes of social communication, fine grained motor skills, and learning and memory with neurophysiological outcomes such as spiking events, spectral power and sleep.

Objectives:

To examine clinically-relevant behavior, neuroanatomy by MRI, and neurophysiology by electroencephalographic (EEG) in our Ube3a deletion rats and an Ube3a overexpression mouse model system.

Methods: N/A

Results: We discovered delayed reflex development, altered social communication, gait abnormalities, and impaired learning and memory in the Ube3a deletion rat model of AS. We also discovered EEG characteristics that are translationally relevant and have been observed in AS and Dup15q clinics, such as abnormal levels of delta and beta power bands. We also discovered that profound neuroanatomical phenotypes.

Conclusion:

Our use of translational innovative outcome measures, like motor skills, social communication, EEG for seizures and power, touchscreen tasks, sleep physiology and motor skills, are required to test the utility of innovative drug designs (i.e. gene therapy, viral vector delivery and/or stem cells), as well as to validate other traditional medicinal therapies (i.e., diet, or pharmaceutics) that may be in the drug discovery pipeline by biotechnological and pharmaceutical companies. Funded by NINDS (R01NS097808) and FAST.