The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans

Abstract

Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common aetiological factors. Rodent models of epilepsy are used to characterize the comorbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, i.e. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the non-epileptic control (NEC) strain. Electrophysiological recordings confirmed the presence of spike-wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety-like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) was subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety-like behaviour, a characteristic reported previously. In addition, using two protocols that differed in shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the conditioned stimuli following unsignalled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning, suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NEC rats showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy.

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

“…These results mirror previous findings where GAERS showed significantly decreased distance travelled in an open field (Bouilleret et al, 2009;Dezsi et al, 2013;Jones et al, 2008;Marks et al, 2016;Powell et al, 2014). Overall, these data suggest that GAERS generally display reduced locomotor activity relative to NECs.…”

“…During a 20 min habituation period in the Y-shaped box prior to the crossmodal sample phase, GAERS displayed spontaneous SWDs resembling those described previously (Marescaux et al, 1992;Marks et al, 2016;Powell et al, 2009;Powell et al, 2014). NECs did not display absence seizures or SWD activity ( Figure 2).…”

“…Of particular relevance, interpretation of the results from the present study are less confounded by the enhanced anxiety in GAERS produced by aversive tasks (see Marks et al, 2016;Marques-Carneiro et al, 2016), and therefore provide an important contribution to the characterization of the behavioral phenotype associated with the GAERS model of CAE. Overall, tactile and visual recognition memory deficits were not as consistent and robust as the deficits observed for the CMOR test.…”

“…GAERS and NECs were first assessed for SWDs with freely moving EEG similar to previous studies (Marks et al, 2016;Powell et al, 2014). During a 20 min habituation period in the Y-shaped box prior to the crossmodal sample phase, GAERS displayed spontaneous SWDs resembling those described previously (Marescaux et al, 1992;Marks et al, 2016;Powell et al, 2009;Powell et al, 2014).…”

“…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). Although progress has been made in characterizing cognitive alterations in GAERS, previous research has observed behavioral alterations using aversive Pavlovian and operant A C C E P T E D M A N U S C R I P T…”