Abstracts

SCN8A encodes the voltage-gated sodium channel (VGSC) Na_v1.6, which regulates neuronal excitability and action potential initiation. SCN8A is differentially expressed in brain tissue from patients with Alzheimer’s disease (AD), a progressive neurodegenerative disease characterized by cognitive impairment and extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tau tangle (NFT) pathologies. Furthermore, up to 42% of AD patients show subclinical epileptiform activity, often with no previous history of seizures, and this epileptiform activity has been linked to worsened cognitive performance in AD patients. Interestingly, a recent genome wide association study identified an AD risk locus on chromosome 12, containing SCN8A, which suggests that SCN8A may contribute to AD. Both amyloid precursor protein (APP) and Aβ have been shown to increase expression of Na_v1.6, which might contribute to neuronal hyperexcitability in AD. Given these observations, we hypothesize that SCN8A may be a genetic modifier for multiple AD phenotypes, such that increasing SCN8A activity in AD will exacerbate disease progression and severity.

To test our hypothesis that increased Scn8a exacerbates AD phenotypes, we crossed mice expressing the human SCN8A R1620L mutation (RL/+) to two well-established AD mouse models: 5xFAD and P301S mice that develop Aβ and NFT pathology, respectively.

Mice that harbor both the 5xFAD/+ and RL/+ mutations (5xFAD/RL) exhibit learning and memory deficits, increased anxiety-like behavior, spontaneous seizures, and premature mortality, with most females dying by 4 months of age. We found that 5xFAD/RL mutants spent significantly less time in the center of the open field apparatus, suggesting increased anxiety-like behavior by 2 months of age in females (N=4-7/genotype) and 4 months of age in males (N = 12-15/genotype). Furthermore, we observed deficits in spatial memory in 4-month-old male 5xFAD/RL mutants compared to 5xFAD/+ mice (N = 8-10/genotype). In addition to behavioral deficits, we also detected greater AD neuropathology (Aβ and GFAP) in the dentate gyrus of male 5xFAD/RL mutants at 4 months of age (N = 6/genotype). Ongoing studies include evaluating behavior and AD neuropathology at other time points. Mice that harbor both the P301S and RL/+ mutations (P301S/RL) are currently undergoing assessments for behavioral deficits, seizure susceptibility, and neuropathological burden.

These results support our hypothesis that SCN8A might be a genetic modifier for AD, such that increasing SCN8A activity in AD will exacerbate multiple phenotypes. The outcomes from our study provide the foundation for exploring SCN8A as a potential therapeutic target for AD and a blueprint for treatment development in other neurological disorders.