Male Specific Behavioural Deficits in a Mouse Model of SCN2A Disorder
Abstract number :
3.071
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2024
Submission ID :
176
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Melody Li, PhD – Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia
Kun Zhou, PhD – Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia
Phan Truong, PhD – Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia
Nikola Jancovski, PhD – Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia
Snezana Maljevic, PhD – Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia
Steven Petrou, PhD – Praxis Precision Medicines, Boston, MA, USA
Rationale: The clinical spectrum associated with SCN2A de novo mutations continues to expand, including developmental and epileptic encephalopathy (DEE) and autism spectrum disorder (ASD). Recent biophysical studies found majority of ASD variants are loss-of-function (LoF). To further understand disease mechanisms, we created a novel mouse model which expresses a missense LoF variant, Scn2a S1758R, and aim to identify disease biomarkers and phenotypes.
Methods: Mice heterozygous for Scn2a p.S1759R, homologous to human variant p.S1758R, were commercially generated. A battery of behavioural assays examining social, cognitive, and motor function, as well as EEG, were deployed in P30-50 mice.
Results: Heterozygous (HET) mice had similar lifespan as their wildtype littermates (WT), and homozygous mice were not obtained. HET mice do not have spontaneous seizures, but EEG recordings revealed a higher number of spikes and overall spectral power across all frequency bands. HET mice are also more susceptible to pro-convulsant induced seizure. While HET mice, regardless of sex, did not show changes in social interaction tests, male HET mice specifically displayed altered cognitive-related behaviours across multiple assays including increased latency to platform in water maze, reduced duration in novel arm of Y-maze, and decreased burying behaviour.
Conclusions: Our study identified multiple behavioural biomarkers in a mouse model that expresses a SCN2A ASD-DEE variant. HET mice showed higher brain hyper-excitability, and cognitive-related deficits were identified in male HET mice.
Funding: -
Basic Mechanisms