Abstracts

Rationale: Absence epilepsy is a heritable human neuropathology characterized by brief (seconds) nonconvulsive seizures associated with behavioral arrest, moderate-to-severe loss of consciousness (absence), and distinct spike-wave discharges (SWDs) with a synchronous onset in the EEG. Genetic models of this disorder have been created by selectively inbreeding rats for absence seizure-like events with similar behavioral and electrical characteristics. However, similar events are also common in outbred laboratory rats, leading to a controversy concerning whether SWDs and behavioral arrest accurately model absence epilepsy, as opposed to reflecting non-pathological brain oscillations. We hypothesized that if SWDs in outbred rats do reflect absence seizures, they would not exist in wild-caught rats due to the pressures of natural selection. Methods: To test this hypothesis, we performed chronic video/EEG recordings of wild-caught rats (Rattus norvegicus similar to Brown Norway; 2 male, 2 female adults and 9 pups born in captivity) and compared these to results obtained from outbred laboratory rats (Long Evans; LE; 10 male) and inbred absence epilepsy models (WAG/Rij; 6 female). SWDs across strains were quantified using pattern recognition. Sensitivity to ethosuximide was also tested. Results: SWDs were frequent in wild-caught rats and remarkably similar to WAG/Rij rats and LE rats. This was reflected in SWD waveform, frequency, duration, circadian rhythmicity, behavioral arrest, and pharmacosensitivity. SWD bursts in all strains were 8-9 Hz with distinct harmonics, and were predominately short (seconds) in duration. SWDs across strains also displayed circadian rhythmicity, with maximum rates in the initial hours of darkness when the animals were awake and active.Similar to absence seizures in the inbred rats, SWDs in both wild and LE rats were associated with immobility. Finally, ethosuximide blocked SWDs across strains. Conclusions: The genes for the SWD/absence-like seizure phenotype are widespread in wild and domesticated rats. SWDs in wild rats - while possibly having similar mechanisms to absence-like seizures – may better approximate normal alpha or mu rhythms. This is consistent with the observation that SWDs are closely associated with an awake but restful state at the onset of darkness. Selective inbreeding has not only increased the incidence of SWDs in GAERS rats, but also completely eliminated them in control strains. Thus, it is perplexing why natural selection has not eliminated SWDs in wild rats, if these SWDs are actual seizures. If SWDs represent absence seizures in wild rats, they must be sufficiently benign as to not influence survival. Others have suggested, however, that these SWDs serve a useful function for survival, such as enhanced somatosensory signal detection. If so, our data may also suggest that absence seizures in humans could reflect a genetic aberration in the activity of thalamo-cortical circuits underlying normal sensory brain function. Funding: Funded by CURE 411446 and CDMRP EP150033