Generation and basic characterization of a gene-trap knockout mouse model of SCN2A

Title: Generation and basic characterization of a gene-trap knockout mouse model of SCN2A with a substantial reduction of voltage-gated sodium channel Nav1.2 expression

Affiliation: National Science Foundation Graduate Research Fellowship Program, Grant/Award Number: DGE-1842166; Indiana Clinical and Translational Sciences Institute, Grant/Award Number: UL1TR002529

Authors: Muriel Eaton,Jingliang Zhang,Zhixiong Ma,Anthony C. Park,Emma Lietzke,Chloé M. Romero,Yushuang Liu,Emily R. Coleman,Xiaoling Chen,Tiange Xiao,Zhefu Que,Shirong Lai,Jiaxiang Wu,Ji Hea Lee,Sophia Palant,Huynhvi P. Nguyen,Zhuo Huang,William C. Skarnes,Wendy A. Koss,Yang Yang

Reference: https://onlinelibrary.wiley.com/doi/10.1111/gbb.12725

We thank Muriel Eaton, first author of this study, for providing us with a summary.

Summary:

What did we do? 

The Yang lab and collaborators developed and charactered a pre-clinical mouse model to study SCN2A deficiency-related disorders caused by loss-of-function or truncation variants.

How did we do it?

The study used a novel gene-trap strategy that allows for enough SCN2A expression of voltage gated sodium channel Nav1.2 for the mice to develop into mature, healthy adults but with notable behaviour abnormalities suggestive of neurodevelopmental disorders.

What did we find?

The pre-clinical mouse model of SCN2A deficiency-related disorders has abnormal behaviour, including profound disruption in innate behaviour, increased anxiety, decreased hot and cold tolerance, and increased repetitive behaviour.

What does this mean?

The robust behaviour abnormalities found in this pre-clinical mouse model make it a good way to test interventions and learn more about how SCN2A deficiency leads to neurodevelopmental disorders.

How do you think this helps future research move forward?

The study used this mouse model to further study the mechanisms behind SCN2A deficiency-related disorders (https://doi.org/10.1016/j.celrep.2021.109495) and found the cellular basis underlying NaV1.2 deficiency-related seizures is an increase in hyperexcitability. This could explain why approximately 20%–30% of individuals with NaV1.2 deficiency also develop seizures.

We are continuing to use this model to test genetic and pharmacological treatments including a dual-AAV gene therapy which is funded by our FamilieSCN2A Foundation Action Potential Grant.

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