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

Abstract

The genetic rat models such as rats of the WAG/Rij strain and GAERS were developed as models for generalized genetic epilepsy and in particular for childhood absence epilepsy. These animal models were described in the eighties of the previous century and both models have, among others, face, construct and predictive validity. Both models were and are currently used as models to predict the action of antiepileptic medication and other experimental treatments, to elucidate neurobiological mechanisms of spike-wave discharges and epileptogenesis. Although the electroencephalagram (EEG)/ electrocorticogram (ECoG) is imperative for establishing absence seizures and to quantify the for absence epilepsy typical spike-wave discharges, monitoring the animals behavior is equally necessary. Here an overview is given regarding the design of drug evaluation studies, which animals to use, classical and new EEG variables, the monitoring and quantification of the behavior of the rats, some pitfalls regarding the interpretation of the data, and some developments in EEG technology.

Sleep Disturbances in Rats With Genetic Pre-disposition to Spike-Wave Epilepsy (WAG/Rij)

“…The epileptogenic process in the thalamocortical circuitry causes SWDs in parallel to changes in sleep spindle EEG activity. This was recently confirmed by Kozák et al (6) in Long Evans rats in which age-related dynamics of SWDs was similar to that in WAG/Rij rats (8)(9)(10). Age-related increase in SWDs in Long Evans rats correlated to a decrease in sleep spindle occurrence rate, suggesting "the possibility of mutually exclusive mechanisms of spindle and SWD generation" (6).…”

“…The group of Anton Coenen and Gilles van Luijtelaar did not find sex-related differences of SWDs in WAG/Rij rats(9,10). Different results were published in 2021: male WAG/Rij rats showed higher mean duration and higher total duration of SWDs than females as measured at the age of 6, 7, 8, 9, and 10 months(46).…”

“…WAG/Rij rats are widely used in fundamental and pre-clinical research in Russia, Hungary, Turkey, Iran, Italy, Hungary, USA, UK, and others (8)(9)(10). Our institution (Institute of Higher Nervous Activity RAS, Moscow, Russia) obtained WAG/Rij rats from Radboud University Nijmegen (Netherlands) in the middle of the 90th years of the last century.…”

Cerebellar Contribution to Absence Epilepsy

“…Some perspectives comprise parallelism between minor AS behavioral manifestations and functionality of the cerebellum extended beyond motor control. Thus, the lately established cerebellar role in cognition [83–85] corresponds to the well-known disruption of consciousness and disturbing informational processes in WAG/rij rats [5, 6, 86, 87].…”

Animal Models of Epilepsy: A Phenotype-oriented Review

“…In addition, the GAERS models also present anxiety-like behavior, social impairment, extinction learning impairment, excessive contextual and cued fear conditioning, and dysfunction in crossmodal recognition memory and visual attention [ 67 ]. Moreover, because of the similar behavioral manifestations, EEG, and genetic features with humans, the WAG/Rij rat models are widely used in the study of genetic absence seizures, especially in children absence seizures [ 69 ]. The WAG/Rij rat usually presents with polypnea, accidental eye-blinks, twitching of the vibrissae, facial myoclonus, and head leaning with classical SWDs [ 69 ].…”