TY - JOUR T1 - Early developmental EEG and seizure phenotypes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0345-20.2020 SP - ENEURO.0345-20.2020 AU - Heather A. Born AU - Luis A. Martinez AU - Amber T. Levine AU - Sarah E. Harris AU - Shubhangi Mehra AU - Wai Ling Lee AU - Scott V. Dindot AU - Kevin R. Nash AU - Jill L. Silverman AU - David J. Segal AU - Edwin J. Weeber AU - Anne E. Anderson Y1 - 2021/12/01 UR - http://www.eneuro.org/content/early/2021/02/01/ENEURO.0345-20.2020.abstract N2 - Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete maternal deletion of the Ube3a gene. It is unknown whether this model recapitulates other aspects of the clinical disorder. We report here the effect of Ube3a maternal deletion in the rat on epileptiform activity, seizure threshold, and quantitative EEG. Using video-EEG monitoring, we assessed spectral power and epileptiform activity early postnatally through adulthood. While EEG power was similar to wildtype (WT) at 1.5 weeks postnatally, at all other ages analyzed, our findings were similar to the AS phenotype in mice and humans with significantly increased delta power. Analysis of epileptiform activity in juvenile and adult rats showed increased time spent in epileptiform activity in AS compared to WT rats. We evaluated seizure threshold using pentylenetetrazol (PTZ), audiogenic stimulus, and hyperthermia to provoke febrile seizures. Behavioral seizure scoring following PTZ induction revealed no difference in seizure threshold in AS rats, however behavioral recovery from the PTZ-induced seizure was longer in the adult group with significantly increased hippocampal epileptiform activity during this phase. When exposed to hyperthermia, AS rat pups showed a significantly lower temperature threshold to first seizure than WT. Our findings highlight an age-dependence for the EEG and epileptiform phenotypes in a preclinical model of AS, and support the use of quantitative EEG and increased delta power as a potential biomarker of AS.Significance Statement Angelman syndrome (AS) is a severe developmental disorder associated with developmental delays, lack of speech, motor and coordination problems, intellectual disability, epilepsy, and abnormal electroencephalographic (EEG) patterns. Here, we present novel findings that the complete deletion of ubiquitin protein ligase E3A (Ube3a), which is an established cause of AS, results in age-depedent increased delta power, epileptiform activity, and altered seizure threshold in the AS rat model. Use of the rat model facilitates early developmental studies, including quantitative EEG analysis and hyperthermia-induced seizures. Our findings support use of the rat model for future pre-clinical studies targeting the development of new, more effective treatment options as well as use of the AS EEG phenotype as a quantitative and translatable biomarker. ER -