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, tau 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 results from cardiorespiratory dysfunction postictally. Functional alterations of neurons and circuits in the dorsal vagal complex, a brainstem area comprised of the nucleus tractus solitarius (NTS), area postrema, and dorsal motor nucleus of the vagus (DMV) have been shown to significantly affect visceral autonomic regulation, and uncontrolled seizures are associated with neural changes in the NTS. The DMV contains parasympathetic motor neurons that are significantly regulated by GABAergic neurotransmission from the NTS. Furthermore, there have been numerous studies that suggest neural activity in the NTS and DMV affects cardiovascular functions. We hypothesize that epilepsy and tauopathy induce alterations in synaptic transmission and intrinsic excitability within brainstem autonomic circuits, specifically in the NTS-to-DMV pathway, that impair autonomic regulation.
Methods:
Transgenic hTau 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 normal human tau. hTau mice begin to develop pTau at ~6 weeks of age, with neurofibrillary tangles apparent at 9 months of age. 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 DMV using whole-cell patch clamp electrophysiology in vitro.
Results:
hTau mice exhibited significantly higher rates of SUDEP compared to both tau knockout and non-transgenic C57BL/6J controls (p < 0.05). Additionally, significantly increased frequencies of both sEPSCs and sIPSCs were observed in DMV neurons of hTau mice with TLE compared to C57 controls, along with altered intrinsic excitability, suggesting enhanced synaptic drive and disrupted autonomic regulation in the presence of tauopathy. Spontaneous seizures are being assessed further to determine the impact of seizure burden on SUDEP risk. Further, the detection of pTau in the hippocampus and brainstem is currently underway.