Abstracts

Rationale: The Wistar Audiogenic Rat (WAR) is a genetically selected strain susceptible to audiogenic seizures (AS) and a model for epilepsy studies. We demonstrated that AS express brainstem-dependent tonic-clonic seizures and audiogenic kindling (AK) is a model of temporal lobe epilepsy. Using neuroethology, EEG, cellular and molecular approaches, we showed that WARs have innate alterations or evoked after AK. WARs have hypertension, tachycardia, increased sympathetic tonus, endogenous anxiety, hyperactivity of the HPA axis and endogenous compulsive grooming. Therefore, as a step forward, the main goals of this study were to characterize WAR strain endogenous cardio-respiratory responses with potential impact for studies of sudden unexpected death in the epilepsies (SUDEP). Methods: Besides the protocols from previous studies from our laboratories, WARs were compared to Wistar animals for cardio-respiratory characterization in the presence of hypoxia (7% O2) and hypercapnia (7% CO2). Behavioral analyses were performed using neuroethological methods. Body plethysmography and temperature sensors were used to obtain, respectively, pulmonary ventilation and body temperature (Tb). Additional evaluations were made in freely moving WAR and Wistar, with long-term ECG recordings to evaluate spontaneous arrhythmias and heart rate variability. Cardiac function was also evaluated using the pressure-volume conductance system in anesthetized rats. Results: In the current studies the ventilatory responses of WARs were attenuated relative to Wistar animals during hypercapnia and hypoxia (p<0.01). This attenuation was associated with behavioral responses. Although decreases in Tb were observed in both groups, the Tb decreases were greater in the WARs during exposure to both hypercapnia and hypoxia (p< 0.05). Electrocardiographic analysis showed that the basal cardiac interval (CI) was similar between WAR and Wistar rats. CI variability, studied by linear and non-linear approaches, strongly suggests an autonomic imbalance with sympathetic predominance in WAR, which is an isolated risk factor for sudden death. Arterial pressure and left ventricle systolic pressure were lower in WAR than in Wistar rats. WAR also exhibited indices of systolic and diastolic dysfunction and a significantly higher number of ventricular ectopic beats when compared to Wistar rats. Conclusions: Our current data on cardio-respiratory and thermoregulatory parameters clearly demonstrate an increase in various risk factors and therefore support the view that the WAR strain is a suitable model for SUDEP. Current and previous data from our laboratories show that with the progression of genetic selection, WAR animals express, besides epilepsy susceptibility, altered brain circuits and cardio-respiratory responses. This makes the strain a reliable genetic model of epilepsy-neuropsychiatry comorbidities and SUDEP. Institutional efforts, with the leadership of our Laboratory, are under way to make the WARs available worldwide. Acknowledgments: FAPESP, FAPESP-Cinapce, PROEX-CAPES, CNPq, FAEPA.