Effects of Mutations in Tau’s Proline Rich Region on Epileptic Activity and Sleep in Mouse Models of Epilepsy

Abstract

AbstractBackgroundGenetic ablation of tau prevents seizures, memory loss, and premature mortality in transgenic mouse models of Alzheimer’s disease, but the exact mechanisms are unknown. We tested the hypothesis that variants in tau’s proline rich domain, which affect binding to SH3‐containing proteins, prevent epileptic activity in epilepsy models.MethodWe used the following lines: 1) AxxA6 (P‐to‐A substitutions in 6th PxxP motif in tau) and 2) R221A: R‐to‐A substitution at amino acid corresponding to 221 in human 2N4R tau. Tau knockout mice were used as a benchmark. We injected kainic acid (25 mg/kg, ip), and analyzed latency to different seizure severity levels (SSL) over 3 hours: 1 to grade 8. We also crossed AxxA6 and R221A mice with the Kv1.1 knockout (Kcna1–/–) model of epilepsy and performed 24‐hour epidural video‐electroencephalography and electromyography in mice ages 5‐8 weeks. We used ex vivo slice electrophysiology and measured burst frequency in CA3 after bath‐applied picrotoxin and 4‐amino‐pyridine.ResultTau knockout mice exhibited higher latency to seizure stages than wildtype mice (WT) after kainic acid injections (p<0.05, One‐way ANOVA), consistent with previous studies. Heterozygous AxxA6 mice showed reduced susceptibility to seizures (n = 4‐6 per genotype; SSL 4‐8: ∼ 9.5 vs WT: 4.5 seconds, p<0.05, One‐Way ANOVA). The heterozygous R221A tau variant decreased mortality in Kcna1 KO mice (p<0.05). Epileptic spikes in Kcna1 KO mice averaged 22 spikes/hour (AxxA6 n = 4, R221A n = 7), and AxxA6 (homozygous and heterozygous) tau variants decreased epileptic activity to ∼2 spikes/hour (p<0.05, One‐Way ANOVA, excluding statistical outliers) in Kcna1 KO mice. Kcna1 KO mice showed a higher percentage in the awake state during light and dark phases compared to WT mice (n = 5, p<0.05, t‐test). The AxxA6 and R221A tau variants did not alter sleep‐wake cycle in Kcna1 KO mice. Kcna1 KO mice showed increase burst frequency in CA3, and heterozygous and homozygous R221A tau variants reduced bursting frequency (p<0.05, One‐Way ANOVA).ConclusionThe AxxA6 and R221A tau lines show partial reduction in seizure susceptibility in models of epilepsy compared to the tau knockout line. The tau protein variants do not affect regulation of the sleep‐wake cycle in the Kcna1 model.