Cellular Determinants of Seizure and Neurobehavioral Phenotypes in Mouse Models of csnk2b-related Neurodevelopmental Disorder
Abstract number :
3.014
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2024
Submission ID :
390
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Abigail Carbonell, MD, PhD – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
Gabriel Jimenez, BS – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
David Lichte, BS – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
Max Erez, BS – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
Mu Yang, PhD – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
Wayne Frankel, PhD – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
Christopher Makinson, PhD – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
Tristan Sands, MD, PhD – Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
Rationale: CSNK2B-related neurodevelopmental disorder is a genetic epilepsy caused by variants in the CSNK2B gene. Patients often present in early childhood with seizures and global developmental delay. In many cases, seizure control is not achieved or requires multiple antiepileptic medications. CSNK2B encodes a subunit of the protein kinase CK2, which is ubiquitously expressed and active throughout life and has been implicated in a host of cellular processes across organ systems. However, the mechanisms through which CSNK2B variants cause neurological manifestations are unknown, and targeted therapies currently do not exist. Approximately half of reported variants are predicted to be protein-truncating, arguing for haploinsufficiency as a likely genetic mechanism.
Methods: Using a novel Csnk2b-floxed line, we generated models of constitutive (Sox2-Cre), central nervous system (CNS)-wide (intracerebroventricular injection of Cre virus), and forebrain-limited (Emx1-Cre) deletion of Csnk2b. We compared growth and survival, developmental milestones, and behaviors related to activity and exploration, learning and memory, and sensorimotor coordination among the models. To test seizure susceptibility, we measured the electroconvulsive thresholds (ECT) in each model using high-frequency and 6-Hz paradigms. We measured Csnk2b expression across the gene in target brain regions with RT-qPCR.
Results: Constitutive heterozygous deletion of Csnk2b in mice resulted in reduced survival, poor growth, and delayed motor development. In ECT testing, constitutive Csnk2b heterozygotes showed increased susceptibility to seizures induced by the 6-Hz paradigm, a model of therapy-resistant epilepsy. Homozygous deletion of Csnk2b yielded viable animals only by postnatal targeting of Csnk2b through Cre injection, and these CNS-wide homozygotes showed severely impaired growth and survival. In behavioral assays, CNS Csnk2b knockdown caused hyperactivity, abnormal exploration, and impaired gait coordination. Targeted forebrain deletion of Csnk2b reproduced the reduced survival, abnormal activity and exploration, and seizure susceptibility observed following constitutive and CNS loss of Csnk2b. RT-qPCR confirmed region-specific loss of Csnk2b expression across exons.
Conclusions: This work represents the first characterization of Csnk2b mouse models focused on disease-relevant phenotypes in development, behavior, and seizure susceptibility. Our results implicate forebrain circuitry (cells expressing Emx1-Cre) in major features of CSNK2B-related disorder, including therapy-resistant epilepsy. These findings will guide future studies on the role of CSNK2B in epileptogenesis and higher brain functions and provide valid disease models for testing targeted therapies to CSNK2B-related disorders.
Funding: N/A
Basic Mechanisms