Abstracts

Rationale:
Angelman syndrome (AS) is a monogenetic developmental disorder that causes unique behavioral phenotypes, seizures, and excessive rhythmic delta and theta electroencephalographic (EEG) activity. AS is commonly caused by deletion or mutation in the maternally imprinted UBE3A gene, which encodes ubiquitin ligase (Ube3a) and is mimicked by the rat model used here. AS children are more likely than the general population to develop febrile seizures (FS) during illness in infancy and may experience FS as the initial seizure event prior to developing epilepsy. In these studies, we evaluated the effects of early life seizures on long-term changes in AS-relevant phenotypes such as epileptiform activity, spectral power, and disrupted sleep in the Ube3a maternal deletion rat model.
Method:
Behavioral evaluation of seizure activity was completed in juvenile and adult wildtype (WT) and AS rats following exposure to chemoconvulsant pentylenetetrazol (PTZ) or stepwise hyperthermia to provoke FS. Additional cohorts were used for video-EEG monitoring at ages ranging from post-natal day (P)8 to one year to assess epileptiform activity, seizures, spectral power, and sleep-wake patterns. EEG and behavior were recorded during baseline activity, seizure induction, and during recovery following induction.
Results:
Similar to the AS population and mouse models, AS rats exhibited increased cortical delta power. Behavioral assessment following PTZ induction showed an age-dependent vulnerability with no difference in seizure threshold in P10, 1 month old, or 2 month old AS rats compared to WT rats, while behavioral recovery from generalized motor seizures at 4.5 months in AS rats was significantly longer than WT rats (p< 0.05), and at 1 year, AS rats showed a decreased latency to first clonus and seizure (p< 0.05). Analysis of percent time in epileptiform activity following PTZ induction at 4.5 months suggested AS rats are more severely affected at 1 hour post-PTZ. When exposed to hyperthermia at P10-11, AS rats showed a lower temperature threshold to FS than WT littermates (p< 0.05), while EEG analysis at later time points suggested short- and long-term changes following early postnatal FS, including increased hippocampal epileptiform activity and delta power.
Conclusion:
Our studies suggest an increased susceptibility and recovery period following seizure induction in AS compared to WT rats, which may contribute to long-term increased epileptiform activity and delta power, particularly following FS. Overall, our seizure threshold studies indicate an age-dependent increased vulnerability to different mechanisms of seizure induction. Studies are ongoing to investigate candidate mechanisms. Determining the impact of seizures in genetic disorders associated with epilepsy is valuable for gaining new insights on mechanisms of disease and therapeutic strategies.
Funding:
:Foundation for Angelman Syndrome Therapeutics, NIH training grant T32 NS043124-15, and American Epilepsy Society and the Pediatric Epilepsy Research Foundation.