Abstracts

Rationale: Absence seizures are the defining seizure type of Childhood Absence Epilepsy (CAE), a disease that is associated with impaired quality of life, developmental difficulties, and a significant probability of progression to tonic-clonic seizures. Seizures feature paroxysmal neuronal activity in widespread brain regions, and are accompanied by distinctive spike-wave discharges (SWDs) on the electroencephalogram (EEG). Current first-line pharmacological treatments do not adequately address the symptoms of CAE, suggesting that greater mechanistic understanding of the disease is required. Such an understanding must be obtained from an animal model with high validity and similarity to human absence epilepsy. Methods: We used a well-established and characterized polygenic rat model, Genetic Absence Epilepsy Rats from Strasbourg (GAERS), to investigate the behavior associated with absence seizures and the neuronal mechanisms of this behavior. Behavior was assessed through sensory detection tasks, in which rats had to respond to a conditioned stimulus during baseline and seizure conditions in order to receive a sucrose reward, and spontaneous licking paradigms, in which rats were encouraged to lick regularly at a spout by the intermittent and unheralded provision of rewards. Neuronal activity accompanying seizures was assessed by EEG monitoring of SWDs during behavioral tests, and comparison with multi-unit and local field potential activity recorded during electrographically similar seizures. Results: Natural licking behavior was decreased by absence seizures (n=17 animals), as compared with activity-matched non-seizure periods. Sensory detection task performance was also impaired during absence seizures relative to non-seizure baseline (4758/5285 responses): animals did not respond, during seizure, to stimuli presented during that seizure (1/625 responses). In both paradigms the degree of behavioral impairment varied from seizure to seizure: a subset of seizures featured preserved or even increased spontaneous licking, while animals were sometimes able to respond to seizure-presented stimuli after cessation of the seizure (albeit more slowly (2.54 ± 0.14 vs. 1.38 ± 0.02s) than during baseline). Seizures with larger initial SWD amplitude were more likely to feature behavioral impairment. These seizures also tended to feature larger cortical multi-unit activity peaks around initiation, due to faster oscillation frequency. Conclusions: GAERS SWDs, similar to human absence seizures, feature impairment of behavioral responses and spontaneous interaction with the environment. The degree of this impairment can vary from seizure to seizure – another trait shared with human absence seizures. This variation also appears to have electrographic correlates, with behaviorally severe seizures featuring increased cortical output and oscillation frequency around seizure initiation. The neuronal (and hemodynamic, see our accompanying poster) determinants of seizure severity may indicate targets for the alleviation of seizure symptoms. Funding: Postdoctoral Fellowship 337053, Epilepsy FoundationNIH R37 NS100901