Seizure expression, behavior, and brain morphology differences in colonies of Genetic Absence Epilepsy Rats from Strasbourg

Abstract

SUMMARYObjective: Originally derived from a Wistar rat strain, a proportion of which displayed spontaneous absence-type seizures, Genetic Absence Epilepsy Rats from Strasbourg (GAERS) represent the most widely utilized animal model of genetic generalized epilepsy. Here we compare the seizure, behavioral, and brain morphometric characteristics of four main GAERS colonies that are being actively studied internationally: two from Melbourne (MELB and STRAS-MELB), one from Grenoble (GREN), and one from Istanbul (ISTAN). Methods: Electroencephalography (EEG) recordings, behavioral examinations, and structural magnetic resonance imaging (MRI) studies were conducted on GAERS and Non-Epileptic Control (NEC) rats to assess and compare the following: (1) characteristics of spike-and-wave discharges, (2) anxiety-like and depressive-like behaviors, and (3) MRI brain morphology of regions of interest. Results: Seizure characteristics varied between the colonies, with MELB GAERS exhibiting the least severe epilepsy phenotype with respect to seizure frequency, and GREN GAERS exhibiting four times more seizures than MELB. MELB and STRAS-MELB colonies both displayed consistent anxiety and depressive-like behaviors relative to NEC. MELB and GREN GAERS showed similar changes in brain morphology, including increased whole brain volume and increased somatosensory cortical width. A previously identified mutation in the Cacna1h gene controlling the Ca V 3.2 T-type calcium channel (R1584P) was present in all four GAERS colonies, but absent in all NEC rats. Significance: This study demonstrates differences in epilepsy severity between GAERS colonies that were derived from the same original colony in Strasbourg. This multiinstitute study highlights the potential impact of environmental conditions and/or genetic drift on the severity of epileptic and behavioral phenotypes in rodent models of epilepsy.

The genetic absence epilepsy rat from Strasbourg as a model to decipher the neuronal and network mechanisms of generalized idiopathic epilepsies

“…Unpublished data. but absent in all NEC rats (Powell et al, 2014) (see below). Environmental conditions may have therefore a significant impact on the expression of the SWD.…”

“…In parallel, we also bred rats from the same outbred Wistar colony in Strasbourg that were free of SWDs and over 5-6 generations we obtained the Non-Epileptic Control (NEC) strain where none of the animals display any seizures (Marescaux et al, 1992a). Both inbred strains have been maintained in Strasbourg and, since 2003, in Grenoble, as well as in Paris, Melbourne, Istanbul and Cardiff (Powell et al, 2014). The GAERS model shares a lot of similarities with another genetic model of absence epilepsy in the rat, the WAG/Rij which was inbred in the United Kingdom, then kept in Rijswijk and later at Nijmegen (The Netherlands) (Depaulis and van Luijtelaar, 2005).…”

“…Their magnitude varies from 300 to 1000 V depending on the brain region that is recorded (see below). When GAERS are maintained in a state of quiet wakefulness, SWDs generally last for about 25 ± 8 s, a duration that varies between individuals, since some animals can display SWDs lasting up to 60 s. They may occur about every minute, depending on the time of the day and recording conditions (Vergnes et al, 1982;Powell et al, 2014) Depaulis and van Luijtelaar, 2005) (Marescaux et al, 1992a). Postictal depression of the LFP is never observed.…”

“…Postictal depression of the LFP is never observed. Seizure characteristics have been shown recently to vary between the colonies: GAERS from Melbourne have SWDs with higher spike frequency but lower occurrence and duration than in the other colonies (Powell et al, 2014) whereas GAERS from the Grenoble colony show the greatest percentage of time spent in seizures. The identified mutation in the Cacna1h gene controlling the CaV3.2 T-type calcium channel (R1584P) was anyway present in all four GAERS colonies, Fig.…”

The T-type calcium channel antagonist Z944 rescues impairments in crossmodal and visual recognition memory in Genetic Absence Epilepsy Rats from Strasbourg

“…Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is an animal model closely resembling CAE. GAERS not only demonstrate recurrent non-convulsive seizures with bilateral and synchronous spike-and-wave discharges (SWD) characteristic of CAE (Marescaux et al, 1992) but also the anxiety and psychiatric-like phenotypes associated with epilepsy (Bouilleret et al, 2009;Dezsi et al, 2013;Jones et al, 2008;Jones et al, 2010;Marks et al, 2016;Powell et al, 2014; but see also Marques-Carneiro et al, 2014). Similar to CAE, GAERS exhibit altered cognition with increased performance observed in fear conditioning and two-way active avoidance tests (Getova et al, 1997;Marks et al, 2016), performance deficits observed for latent inhibition and extinction of conditioned fear (Marks et al, 2016), and delayed acquisition of spatial reference and working memory in a Morris water maze (Marques-Carneiro et al, 2016).…”