Spontaneous Recurrent Absence Seizure-like Events in Wild-Caught Rats

Abstract

Absence epilepsy is a heritable human neurological disorder characterized by brief nonconvulsive seizures with behavioral arrest, moderate-to-severe loss of consciousness (absence), and distinct spike-wave discharges (SWDs) in the EEG and electrocorticogram (ECoG). Genetic models of this disorder have been created by selectively inbreeding rats for absence seizure-like events with similar electrical and behavioral characteristics. However, these events are also common in outbred laboratory rats, raising concerns about whether SWD/immobility accurately reflects absence epilepsy as opposed to "normal" rodent behavior. We hypothesized that, if SWD/ immobility models absence seizures, it would not exist in wild-caught rats due to the pressures of natural selection. To test this hypothesis, we compared chronic video/electrocorticogram recordings from male and female wild-caught (Brown-Norway [BN]) rats to recordings from laboratory outbred BN, outbred Long-Evans, and inbred WAG/Rij rats (i.e., a model of absence epilepsy). Wild-caught BN rats displayed absence-like SWD/immobility events that were highly similar to outbred BN rats in terms of spike-wave morphology, frequency, diurnal rhythmicity, associated immobility, and sensitivity to the anti-absence drug, ethosuximide; however, SWD bursts were less frequent and of shorter duration in wild-caught and outbred BN rats than the outbred Long-Evans and inbred WAG/Rij strains. We conclude that SWD/immobility in rats does not represent absence seizures, although they appear to have many similarities. In wild rats, SWD/immobility appears to represent normal brain activity that does not reduce survival in natural environments, a conclusion that logically extends to outbred laboratory rats and possibly to those that have been inbred to model absence epilepsy. Significance StatementSpike-wave discharges (SWDs), behavioral arrest, and diminished consciousness are cardinal signs of seizures in human absence epilepsy and are used to model this disorder in inbred rats. These characteristics, however, are routinely found in outbred laboratory rats, leading to debate on whether SWD/immobility is a valid model of absence seizures. The SWD/immobility events in wild-caught rats appear equivalent to those found in outbred and inbred rat strains, except for lower incidence and shorter durations. Our results indicate that the electrophysiological and behavioral characteristics of events underlying hypothetical absence epilepsy in rodent models are found in wild rats captured in their natural environment. Other criteria beyond observation of SWDs and associated immobility are required to objectively establish absence epilepsy in rat models.

Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes

“…SWDs were significantly more prevalent and had longer durations in Syngap +/Δ-GAP rats when compared to age-matched WT littermates, and similar to previous reports, these SWDs do not occur during our behavioural tasks and were suppressed by ethosuximide (Shaw, 2004(Shaw, , 2007Terzioglu et al, 2006). Although SWDs were found in our WT animals, these were at a frequency similar to previous reports (Taylor et al, 2019). Moreover, the higher incidence of SWDs in mutants suggests that the deletion of the C2/GAP domain in rats drives cortical networks to a state of hyperexcitability leading to absence-like electrophysiological phenomena.…”

Establishing Drug Effects on Electrocorticographic Activity in a Genetic Absence Epilepsy Model: Advances and Pitfalls

“…A combined EEG video study showed that during the cortical expressed SWDs WAG/ Rij rats show head tilting, twitching of the vibrissae, accelerated breathing, and occasional eye blinks, and facial myoclonus in otherwise immobile animals (van Luijtelaar and Coenen, 1986). Close inspecting of the EEG oscillations as presented in Taylor et al (2019) shows that only a minority of the illustrated SWDs in the wild rats could classify as SWDs according to our criteria and characteristic features. Relevant and typical is that SWDs appear as bilateral symmetrical generalized, minimal duration 1 s, asymmetric morphology with a sharp large amplitude negative peak with a duration between 25 and 35 ms, this peak is most pronounced expressed at the frontal cortex and a clear negative wave (40-60 ms), less well expressed at the frontal cortex but more at the thalamic VPM, with a "sudden" appearance from a normal appearing background and without a waxing and waning pattern).…”

“…A relevant question that was recently raised again is whether all oscillations in the 8 Hz domain, mimicking to some extent the SWDs in GAERS and WAG/Rij rats and are known for a long term to be present in different outbred strains of rats (Willoughby and Mackenzie, 1992;Marescaux et al, 1984;van Luijtelaar et al, 1994) and now noticed in wild rats, should be indeed considered as genuine epileptic SWDs (Taylor et al, 2017;Taylor et al, 2019). First, WAG/Rij rats have clinical concomitants during the SWDs, they are mild, and might be easily overlooked.…”

Сучасні Принципи Та Технічне Забезпечення Досліджень На Моделі Генетичної Форми Абсансної Епілепсії

“…Важливим питанням, що залищаєтьcя відкритим, є визначення ритмічних розрядів частотою 8 Гц як таких, що мають відношення до СХР у щурів ліній GAERS та WAG/Rij, а також у генетично похідних змішаних ліній [39,80,98]. Подібне питання стає важливим при визначенні природи подібних СХР, що останнім часом зареєстровано у безпородних диких ліній щурів [69,70].…”

“…Так, одночасна реєстрація відео-та ЕЕГ засвідчила, що на тлі СХР, які реєстрували в корі головного мозку у WAG/Rij щурів спостергіаються характерні посмикування голови та вібрис, прискорене дихання, посмикування повік із закриттям ока, клонуси мязів морди на тлі завмирання тварини [76]. Аналіз ЕЕГ-картини наведений [70] свідчить, що тільки меншість ілюстрованих автором СХР у диких щурів може бути визнане в якості СХР. Зокрема для визнання приналежності до СХР потрібна одночасна, симетрична та білатеральна їх поява з мінімальною тривалістю комплексів в одну секунду, а також із характерною МЕДИЧНА ІНФОРМАТИКА МЕДИЧНА ІНФОРМАТИКА ТА ІНЖЕНЕРІЯ морфологією окремих розрядів, до якої відносяться гострий високоамплітудний спайк негативної полярності тривалістю 25-35 мс.…”