Epileptogenic Mechanisms and Treatment Responses in a Gain-of-function GABRD Mouse Model of Epilepsy
Abstract number :
1.232
Submission category :
2. Translational Research / 2D. Models
Year :
2024
Submission ID :
746
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Khaing Phyu Aung, M.B., B.S., MSc, PhD – The University of Melbourne, Florey Institute of Neuroscience and Mental Health
Chaseley McKenzie, BS – The University of Melbourne, Florey Institute of Neuroscience and Mental Health
Ming Soh, PhD – The University of Melbourne, Florey Institute of Neuroscience and Mental Health
Alibek Kuanyshbek, M.B., B.S., MSc – The University of Melbourne, Florey Institute of Neuroscience and Mental Health
Hian Lee, M.B., B.S. – The University of Melbourne, Florey Institute of Neuroscience and Mental Health
Nathan Absalom, PhD – Faculty of Medicine and Health, The University of Sydney
Rikke Møller, MD – Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre
Mary Chebib, PhD – Faculty of Medicine and Health, The University of Sydney
Philip Ahring, PhD – Faculty of Medicine and Health, The University of Sydney
Christopher Reid, PhD – The University of Melbourne, Florey Institute of Neuroscience and Mental Health
Rationale: Pathogenic variants in GABAA receptor subunits play a prominent role in genetic epilepsy. A recent clinical study identified gain-of-function (GOF) GABRD variants as the cause of generalized epilepsy and severe neurodevelopmental disorders. However, the underlying cellular and network basis of the disease remains unclear. To address this, we engineered a mouse model based on the human GOF GABRD p.L260V variant. This specific variant is associated with a clinical phenotype characterized by early onset myoclonic and generalised tonic-clonic seizures, behavioural abnormalities, intellectual disability, and severe developmental delay. We hypothesize that the p.L260V variant causes increased tonic inhibition and that the mouse model will recapitulate key patient characteristics. Hence, this study sought to characterize the mouse model, confirm the GOF mechanism caused by the GABRD variant at the synaptic level, and test potential treatment options.
Methods: A mouse model was engineered based on the human GOF GABRD p.L260V variant using standard CRISPR techniques. Using the mouse model, we have performed 1) survival rate monitoring (until P100), 2) proconvulsant challenge, 3) electroencephalogram (EEG) recordings, 4) behavioural testing, and 5) whole-cell electrophysiology recordings between littermates. GabrdL260V mice were also used to screen the effects of several anti-epileptic drugs. Survival analysis was done using a Mantel-Cox log-rank test. Student’s t-test was used for comparison between two groups. Statistical significance was set at P< 0.05.
Translational Research