Seizures and Behavioral Phenotypes in AS Mice and Use of this Information in Preclinical Trials

Quick Overview

Dr. Anne Anderson from Baylor College of Medicine presented her work on seizures and behavioral phenotypes in Angelman syndrome (AS) mice at the 2015 FAST Science Summit. She discussed the challenges of working with AS mouse models and the variability in their phenotype. Dr. Anderson’s lab conducted behavioral and EEG studies to characterize the seizures and abnormal behavior in the mice. They found that the Black 6 AS mice had abnormal EEG activity and generalized polyspike seizures, while the 129 AS mice had audiogenic seizures and increased susceptibility to kainic-induced seizures. However, treatment with the Neuren compound NNZ-2566 did not rescue the behavioral or seizure phenotypes in the AS mice. Dr. Anderson also mentioned the potential use of pig models for future studies and the importance of preclinical trials in developing therapeutics for AS.

Introduction

Dr. Anne Anderson, a neurologist and epileptologist from Baylor College of Medicine, presented her work on the FIRE team at the 2015 FAST Science Summit. In her presentation, she discussed her research on seizures and behavioral phenotypes in Angelman syndrome (AS) mice and the use of this information in preclinical trials.

Background

Dr. Anderson explained that her clinical focus is epilepsy, and she runs the epilepsy clinic at Baylor College of Medicine. She was recruited to the FIRE team by Ed Weeber, who she had previously worked with during her postdoctoral period. Dr. Anderson’s lab had to spend a significant amount of time getting the AS mice up and running in their lab, as there were challenges with the variability of the phenotype depending on the background strain of the mice.

Importance of Preclinical Studies

Dr. Anderson emphasized the importance of preclinical studies in translating research to the bedside. These studies are necessary to identify novel targets for pharmaceuticals and to screen compounds for efficacy before testing them in humans. Regulatory boards also require preclinical studies to support the use of new treatments. Dr. Anderson highlighted a study from Art Beaudet’s lab that characterized the phenotype of the AS mice, which served as a basis for further research.

EEG and Seizure Phenotypes in AS Mice

Dr. Anderson’s lab focused on evaluating EEG activity and seizure phenotypes in the AS mice. They found that the AS mice had abnormal EEG activity, similar to what is seen in individuals with AS. The mice also exhibited spontaneous seizures and increased susceptibility to convulsion-induced seizures. Dr. Anderson showed EEG traces and explained the different frequencies and abnormalities observed in the AS mice.

Behavioral Phenotypes in AS Mice

In addition to EEG and seizure studies, Dr. Anderson’s lab also performed behavioral screening in the AS mice. They found that the Black 6 AS mice had decreased locomotor activity, abnormal repetitive behavior, and motor coordination deficits. These behavioral deficits correlated with the known phenotype of AS. Dr. Anderson mentioned that the 129 AS mice had audiogenic seizures and increased susceptibility to kainic-induced seizures.

Screening Therapeutics

Dr. Anderson discussed the screening of a compound called NNZ-2566 in the AS mice. This compound had shown promising results in Fragile X and Rett syndrome, and the FIRE team wanted to test its efficacy in AS. However, the compound did not rescue the behavioral or seizure phenotypes in the AS mice. Dr. Anderson mentioned that the team is ready to move on to screening other compounds and treatments.

Future Directions

Dr. Anderson expressed excitement about characterizing seizures and epilepsy in other models, such as the pig model. She also mentioned potential studies on sleep, inflammation, and the use of biomarkers for screening therapeutics. Dr. Anderson acknowledged the support of the FAST-FIRE funding and the collaboration with the FAST team, as well as the inspiration she receives from individuals with AS and their families.

Conclusion

Dr. Anne Anderson’s presentation highlighted the importance of preclinical studies in understanding the phenotypes of AS mice and screening potential therapeutics. Her research on seizures and behavioral phenotypes provides valuable insights for future studies and the development of treatments for Angelman syndrome.