A cacna1a/cacng2 Digenic Mouse Model for Childhood Absence Epilepsy with Altered Social Novelty Preference
Abstract number :
1.062
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2024
Submission ID :
1072
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Qinglong Miao, PhD – Baylor College of Medicine
James Okoh, PhD – Baylor College of Medicine
Mauro Costa-Mattioli, PhD – Baylor College of Medicine
Jeffrey Noebels, MD. PhD – Baylor College of Medicine
Rationale: Epilepsy is a prevalent neurological disorder characterized by recurrent seizures, affecting millions of individuals worldwide. Among various forms of epilepsy, childhood absence epilepsy (CAE) is particularly common in pediatric patients and is believed to have a strong genetic component. Despite its familial clustering, CAE does not follow a simple Mendelian inheritance pattern, suggesting a complex polygenic nature. In addition to seizure activity, cognitive impairments and social behavior abnormalities are frequently observed in neurodevelopmental disorders, including CAE. However, the behavioral aspects of developmental and epileptic encephalopathy (DEE) and their response to anti-seizure medications are not well understood.
Methods: EEG, Mouse Genetics, Immunohistochemistry and RT-PCR
Results: In this study, we investigated the combined effects of heterozygous mutations in two human CAE and/or ASD (autism spectrum disorder)-associated genes, CACNA1A and CACNG2, which encode the α-subunit of P/Q-type calcium channels (Cav2.1) and a transmembrane AMPA receptor regulatory protein (TARP) named stargazin, respectively. Using a digenic mouse model (DiGstg+Ca1A) carrying both mutations, we demonstrated that these genetic alterations led to the development of CAE and alterations in social novelty preference. Furthermore, we evaluated the efficacy of ethosuximide, a commonly prescribed anti-CAE medication, in this mouse model. While ethosuximide successfully suppressed absence seizures, it failed to restore social novelty preference in the DiGstg+Ca1A mice. This observation aligns with clinical findings that neurocognitive impairments persist in CAE patients, even with successful seizure control under first-line anti-seizure medications like ethosuximide.
Conclusions: Our findings present the first digenic animal model that replicates the complex inheritance patterns observed in human CAE. The DiGstg+Ca1A mice exhibit altered social behavior that is resistant to ethosuximide treatment, mirroring the condition observed in human patients. This study provides valuable insights into the intricate heredity of CAE and lays the foundation for the development of novel therapeutic interventions to address this disorder in the future.
Funding: NIH/NINDS R01 NS29709 (JLN).
Basic Mechanisms