Abstracts

Rationale: Epileptic seizures are a key feature of Tuberous Sclerosis Complex (TSC), putting these patients at risk for sudden unexpected and unexplained death in epilepsy (SUDEP). SUDEP is the most common cause of death for TSC patients. However, little is known about the underlying mechanisms of SUDEP in this population. We have previously shown early fatality in other mouse models of epilepsy is due to seizure-induced apnea (SIA) that is initiated during the tonic phase. Therefore, we hypothesize that this SIA is the cause of SUDEP in Tsc1^Syn1-Cre mice as well.

Methods: We crossed Syn1-Cre mice (Jax #003966) and floxed-TSC1 mice (Jax #038428) to produce mice that were heterozygous for Syn1-Cre and homozygous for floxed-TSC1 (Tsc1^Syn1-Cre mice). When the mice reached three weeks of age, we performed a stereotaxic surgery to implant headsets to chronically record electroencephalogram (EEG), electrocardiogram (ECG), and video. After a short recovery period, Tsc1^Syn1-Cre mice were then placed in whole body plethysmography chambers to record breathing where the headsets were connected via custom pre-amplified cables to our amplification (Grass Neurodata) and digitization (Powerlab) system. The LabChart 7 program was used to record all biosignals and video. Data were analyzed in Spike2.

Results: Tsc1^Syn1-Cre mice routinely displayed seizures that included spike wave discharges (SWD), convulsions, and altered breathing and cardiac function. A seizure experienced early in the recording session demonstrated SWDs, bradycardia, and suppressed breathing (Fig. 1). A few days later, the mouse experienced a fatal seizure (Fig. 2). By this point, breathing was very minimal and below the noise level of the pressure transducer, so it is not included. However, the mouse experienced a tonic phase prior to its death, which is seen in the ECG lead. The EEG signals during the tonic phase showed no SWD or any cortical activity that would resemble a seizure.

Conclusions: We present evidence that indicates that seizures produce fatality in TSC mice. In addition, the mechanism of death appears similar to that of other mouse models we have studied where SIA is initiated during the tonic phase and breathing does not recover, leading to death. Once the mechanism of SIA is better understood, more targeted treatments can be developed to help TSC patients.

Funding: DOD TS220001
TSC Alliance