Scn8a, encoding the voltage-gated Na+ channel Nav1.6, is primarily expressed in neurons and glia. Nav1.6 plays a vital role in the central nervous system by regulating the electrical excitability of neurons. It is involved in processes like action potential generation and propagation, thus being crucial for normal neural function [2,3]. Genetic models, such as mouse models, are valuable for studying Scn8a due to the difficulty of directly studying human neurons.

Mouse models with Scn8a null mutations (e.g., Scn8a(med) and Scn8a(medTg)) have a short lifespan of 21-24 days, while those with incomplete mutations (e.g., Scn8a(medJ) and Scn8a(medJo)) or knockout only in cerebellar Purkinje cells can survive to adulthood. In these mutants, the resurgent sodium current underlying the repeated firing of Purkinje cells is reduced, leading to greatly decreased spontaneous activity of Purkinje cells and analogous cartwheel cells in the dorsal cochlear nucleus. There is also an up-regulation of GABA(A) receptors in regions to which Purkinje cells project, potentially compensating for their decreased activity [3]. Additionally, two mouse models carrying patient mutations N1768D and R1872W were generated. The conditional R1872W mutation, activated by CRE recombinase, allowed for the study of the mutation's effects on different neuron classes and at different postnatal development stages. Preclinical drug testing in these models supported new therapies for the associated disorder [1].

In conclusion, Scn8a is essential for maintaining normal neural excitability, especially in the context of action potential-related processes. Mouse models, including knockout and conditional knockout models, have been instrumental in revealing its role in neural function and have provided a basis for preclinical drug testing in diseases related to Scn8a mutations, such as epileptic encephalopathy [1,3].

References:

1. Meisler, Miriam H. . SCN8A encephalopathy: Mechanisms and models. In Epilepsia, 60 Suppl 3, S86-S91. doi:10.1111/epi.14703. https://pubmed.ncbi.nlm.nih.gov/31904118/

2. Talwar, Dinesh, Hammer, Michael F. 2021. SCN8A Epilepsy, Developmental Encephalopathy, and Related Disorders. In Pediatric neurology, 122, 76-83. doi:10.1016/j.pediatrneurol.2021.06.011. https://pubmed.ncbi.nlm.nih.gov/34353676/

3. Chen, Kejian, Godfrey, Donald A, Ilyas, Omer, Xu, Jiansong, Preston, Todd W. 2009. Cerebellum-related characteristics of Scn8a-mutant mice. In Cerebellum (London, England), 8, 192-201. doi:10.1007/s12311-009-0110-z. https://pubmed.ncbi.nlm.nih.gov/19424768/