Abstracts

Rationale: Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns, including excessive rhythmic delta and theta activity and epileptiform discharges as key features of the disease. The most common genetic cause of AS is deletion or mutation in the maternally imprinted Ube3a gene, encoding ubiquitin ligase (Ube3a), which is mimicked in the rat model used here. Compared to the general population, AS children are more vulnerable to febrile seizures (FS) during illness in infancy and may experience FS as the initial seizure event prior to developing epilepsy. Determining the impact of seizures in the course of a genetic disease is necessary to better model the progression of human disease and gain new insight on potential therapeutic strategies. In our study, we sought to characterize the effect of the AS genetic lesion in combination with induced seizures on threshold and subsequent EEG activity in a novel Ube3a maternal deletion rat model. Methods: Juvenile and adult wildtype (WT) and AS rats were used to evaluate seizure threshold by observing behavior after exposure to either the chemoconvulsant pentylenetetrazol (PTZ), audiogenic stimulus, or gradually increased temperature to induce FS. Additional cohorts were implanted with cortical and hippocampal-depth electrodes for video-EEG monitoring as early as post-natal day (P) 8 or in adulthood to assess epileptiform events, seizures, and spectral power. EEG activity was recorded during baseline conditions, during PTZ or FS induction, and following induction during recovery. Results: As in the AS population and mouse models, AS rats exhibit abnormal EEG activity, however behavioral assessment following PTZ induction did not reveal a decreased seizure threshold in 1 month AS rats. Compared to WT, behavioral recovery from generalized motor seizures at 4.5 months in AS rats was significantly longer (p<0.05; n=14) and at 1 year AS rats showed a decreased latency to first clonus and seizure (p<0.05; n=22-27). Unlike mice, juvenile AS rats typically did not develop generalized audiogenic seizures but did experience decreased time to immobility after the stimulus began and increased time to recover following stimulus end (p<0.05; n=12). When exposed to hyperthermia at P10-11, AS rats showed a lower temperature threshold to FS than WT littermates (p<0.05; n=5-10), and EEG analysis suggested both short- and long-term changes following early postnatal FS including abnormal hippocampal spiking and increased spectral power (n=1-2). Conclusions: These studies suggest age-dependent increased vulnerability to PTZ-induced seizures and an increased severity/duration of altered EEG and behavior following induction in AS compared to WT rats. The increased susceptibility to seizure induction in AS rats may contribute to long-term changes in EEG activity, particularly with regards to FS. Overall, our seizure threshold studies indicate increased vulnerability to different mechanisms of seizure induction that is age-dependent. Funding: Foundation for Angelman Syndrome Therapeutics, NIH training grant T32 NS043124-15, and American Epilepsy Society and the Epilepsy Foundation.