Abstracts

Rationale: Status epilepticus (SE) is a prevalent neurological disorder, which is associated with significant morbidity, including the development of epilepsy and mortality. Studies indicate that lethal cardiac arrhythmias contribute to death following SE as well as sudden unexpected death in epilepsy (SUDEP). A range of potentially lethal cardiac arrhythmias are observed in epilepsy and are indicative of underlying autonomic nervous system (ANS) dysfunction. Models of sympathoexcitation exhibit increased ANS tone and elevated levels of angiotensin II (ANG II) in the brain. ANG II binds to both angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptors with equal affinity, and, in models of sympathoexcitation, there is an increase in AT1 receptor levels and decrease in AT2 receptor levels in the rostral medulla. Similarly, studies in epilepsy models have shown increased ANG II levels in the brainstem and alterations in ANS tone, indicating a potential mechanism for elevated ANS tone in patients with epilepsy. Methods: Intrahippocampal (IH) administration of kainate, a glutamate analog, results in SE, followed by the development of chronic, spontaneous recurring seizures (epilepsy) and closely models what occurs in humans with temporal lobe epilepsy. To simultaneously investigate alterations in EKG and video synchronized EEG signals following SE, male C57BL6J mice were implanted with an IH cannula and six electrodes at 2-4 months of age. Baseline EKG and EEG activity were recorded. Then, animals received saline or kainate via IH cannula and monitored for two weeks. At two weeks, tissue was harvested and using immunohistochemistry, probed for levels of tyrosine hydroxylase and AT1/AT2 receptors. Results: Recordings showed ictal bradycardia and post-ictal tachycardia, which had been described in other mouse models of SE, as well as humans. SE animals exhibited decreased interictal beat-to-beat variability however there was no difference in heart rate 14 days following SE. Animals exhibited significant increases in the number of escape rhythms and arrhythmic events (n=6, p Conclusions: Our mouse model recapitulates changes that are observed in human TLE. Although average heart rate was not different for saline and SE animals, amount of potentially lethal arrhythmias observed and beat-to-beat variations in heart rate indicate ANS dysfunction ictally and interictally. Interestingly, the arrhythmias were observed commonly during sleep and more than half of all cases of SUDEP are reported to occur during sleep. Immunohistochemistry was used to identify the rostral medulla (using tyrosine hydroxylase) and probe for the levels of AT1 and AT2 receptors. Our preliminary findings illustrate a decrease in both AT1 and AT2 receptors as well as the ratio of AT1:AT2. These findings indicate a potential mechanism for ANS dysfunction. We are continuing to investigate the mechanisms of ANS dysfunction following SE as it may be fruitful in providing greater understanding as well as treatments to prevent future cases of SUDEP. Funding: n/a