Abstracts

Rationale: Angelman syndrome (AS) is a monogenetic neurodevelopmental disorder with unique behavioral phenotypes and seizures as key features of the disease. The most common genetic cause of AS is the deletion or mutation in the maternally imprinted Ube3a gene, encoding ubiquitin ligase (Ube3a), which is mimicked in the rat model used here. Data from the AS population and AS mouse models has revealed abnormal electroencephalographic (EEG) patterns including excessive rhythmic delta and theta activity and epileptiform discharges. In our study, we sought to characterize the effect of the AS genetic lesion on electroencephalographic (EEG) activity and seizure threshold in a novel Ube3a maternal deletion rat model of AS. Methods: Wild-type (WT) and AS rats were implanted with cortical and hippocampal-depth electrodes for video-EEG monitoring during early development as early as post-natal day 8 and in adulthood to assess epileptiform activity and spectral power. EEG activity was recorded for 2 hour sessions during pre-weaning ages or for 48-72 hour sessions at post-weaning ages and examined for abnormal epileptiform activity and spectral analysis. At post-weaning ages, recordings were evaluated during both light and dark activity. Additional cohorts were used to evaluate seizure threshold by using the chemoconvulsant pentylenetetrazol (PTZ) during early post-natal development and in adults (1 mo: n=17; 2.5 mo: n=5-7; and 4 mo: n=14). Results: Spectral EEG power analysis indicated that, much like our previous findings in an AS mouse model and in humans with AS, juvenile AS rats had significantly increased spectral cortical EEG power primarily driven by increased delta frequencies (p‹0.05 at 1-3 Hz; n=3-5/group). Spectral analysis of hippocampal EEG also showed increased delta frequency power (p‹0.05 at 1-2 Hz; n=3-5/group). Assessment of behavior following PTZ seizure induction did not reveal a decreased seizure threshold in adult AS rats, however behavioral recovery from generalized motor seizures was significantly longer when compared to WT (p‹0.05; n=14/group). Conclusions: In addition to the longer lasting effect of PTZ on behavioral recovery, our findings indicate that the AS rat model shows electrographic abnormalities. The differences in EEG spectral power found in the rat model are similar to symptoms of AS in the human disease, which lends support to the use of spectral analysis and increased delta power in EEG activity as a potential biomarker of AS. Funding: Foundation for Angelman Syndrome Therapeutics Integrative Research Environment and NIH training grant T32 NS043124-15