Abstracts

Rationale: Hyperphosphorylated tau (pTau) aggregates and other tauopathies have been observed in patients with epilepsy. Tau hyperphosphorylation increases the excitability of neuronal networks and has been shown to promote susceptibility to seizures in animal models of tauopathy. Conversely, the removal of tau with genetic deletion or suppression reduces seizure burden and improves survival in animal models of induced seizure and genetic epilepsies. One outcome of uncontrolled seizures is Sudden Unexpected Death in Epilepsy (SUDEP). SUDEP accounts for ~17% of deaths in patients with epilepsy and is thought to arise from cardiorespiratory dysfunction. The brainstem nucleus tractus solitarius (NTS) is a critical regulator of visceral function and dysregulation of the NTS can lead to breathing and heart rate dysregulation, and uncontrolled seizures are associated with neural changes in the NTS. We tested the hypothesis that tauopathy contributes to SUDEP in a mouse model of acquired temporal lobe epilepsy (TLE) that lead to comorbidities leading to SUDEP.

Methods: Transgenic hTau and tau knockout (KO) mice were used to examine TLE and the pathological role of tau. Native murine tau is deleted in hTau mice and replaced with all 6 isoforms of human tau. hTau mice begin to develop pTau at ~6 weeks of age, with neurofibrillary tangles apparent at 9 months of age. The tau KO mice have no murine or human tau expression. Tau KO, hTau, and non-transgenic control mice were given intrahippocampal kainic acid (IHK) injections to induce status epilepticus (SE) and, after a latent period, acquired TLE with spontaneous recurrent seizures (SRS). SE and SRS were assessed with video monitoring. Additionally, we measured cellular excitability in the NTS using whole-cell patch clamp electrophysiology in vitro.

Results: We found that the hTau mice died at significantly higher rates of SUDEP compared to tau KO and non-transgenic control mice (p< 0.05). Surprisingly, there was a sex difference observed in SUDEP rate among hTau mice (p< 0.05), as well as differences in neuronal network properties in the NTS between epileptic wildtype and hTau mice. Spontaneous seizures are being assessed to determine the impact of seizure burden on SUDEP risk. Further, the detection of pTau in the hippocampus and brainstem is currently underway using phospho-tau specific antibodies to inform interpretation of ptau expression and its role in SUDEP.