Research PaperAltered gene expression profile in a mouse model of SCN8A encephalopathy

- The onset of seizures in a mouse model of SCN8A encephalopathy is accompanied by changes in gene expression in the brain.
- The pattern of altered brain gene expression results, in part, from reactive astrocytosis in the hippocampus.
- In the absence of seizures, there were no observed changes in the expression profiles of mice with the Scn8a mutation.
- Elevated levels of the neuropeptides NPW and galanin may play a protective role during the response to seizures.
- There is no change in transcript levels for Scn8a or the other voltage-gated ion channel genes in the Scn8a mutant mouse.

SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Nav1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3-fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy.