Sociability impairments in Genetic Absence Epilepsy Rats from Strasbourg: Reversal by the T-type calcium channel antagonist Z944

Highlights

• Sociability was tested in a rat model of absence epilepsy.

• Sociability was impaired in female rats with absence seizures.

• The T-type calcium channel blocker Z944 reversed the sociability deficits.

• Z944 produced sociability deficits in female animals of the control strain.

Abstract

Childhood absence epilepsy (CAE) is associated with interictal co-morbid symptoms including abnormalities in social behaviour. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a model of CAE that exhibits physiological and behavioural alterations characteristic of the human disorder. However, it is unknown if GAERS display the social deficits often observed in CAE. Sociability in rodents is thought to be mediated by neural circuits densely populated with T-type calcium channels and GAERS contain a missense mutation in the Cav3.2 T-type calcium channel gene. Thus, the objective of this study was to examine the effects of the clinical stage pan-T-type calcium channel blocker, Z944, on sociability behaviour in male and female GAERS and non-epileptic control (NEC) animals. Female GAERS showed reduced sociability in a three-chamber sociability task whereas male GAERS, male NECs, and female NECs all showed a preference for the chamber containing a stranger rat. In drug trials, pre-treatment with 5 mg/kg of Z944 normalized sociability in female GAERS. In contrast, female NECs showed impaired sociability following Z944 treatment. Dose-dependent decreases in locomotor activity were noted following Z944 treatment in both strains. Treatment with 10 mg/kg of Z944 altered exploration such that only 8 of the 16 rats tested explored both sides of the testing chamber. In those that explored the chamber, significant preference for the stranger rat was observed in GAERS but not NECs. Overall, the data suggest that T-type calcium channels are critical in regulating sociability in both GAERS and NEC animals. Future research should focus on T-type calcium channels in the treatment of sociability deficits observed in disorders such as CAE.

Introduction

Childhood absence epilepsy (CAE) is characterized by losses in consciousness that can co-occur with mild clonic movements and automatisms during bilateral spike and wave discharges (SWD's) concomitant with seizure activity (Pavone et al., 2001). Similar to other epilepsies, CAE is associated with interictal co-morbid impairments including cognitive (Caplan et al., 2009, Henkin et al., 2005, Killory et al., 2011, MacEachern et al., 2017, Mandelbaum and Burack, 1997, Pavone et al., 2001) and language deficits (Caplan et al., 2009), as well as social behaviour abnormalities (Caplan et al., 2009). The GAERS model of absence epilepsy, but not its related NEC strain, exhibits similar SWD characteristics of CAE (Marescaux et al., 1992, Tringham et al., 2012). Previous research has shown that GAERS also display the cognitive 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., 2016a, Marks et al., 2016b, Powell et al., 2014, but see also Marques-Carneiro et al., 2014); however, it is unknown whether they demonstrate the social deficits observed in CAE. Social deficits occur in approximately 23% of CAE patients (Caplan et al., 2008). In adulthood, individuals with absence epilepsy are significantly more socially isolated (Olsson and Campenhausen, 1993). These social deficits occur regardless of seizure control (Nickels, 2015). Therefore, the first objective of the present study was to assess sociability in the GAERS model.

T-type calcium channels are abundantly expressed in the circuits implicated in mediating rodent social behaviour including the amygdala, olfactory bulb, piriform cortex, and lateral septum (Ferguson et al., 2001, Talley et al., 1999). Morphometric abnormalities have been observed in the amygdala of GAERS further suggesting the possibility of disrupted social behaviour in these animals (Bouilleret et al., 2009). Seizures in GAERS are produced by abnormalities in thalamocortical circuity at least in part due to gain-of-function missense mutation in the Cav3.2 T-type calcium channel gene (Cain et al., 2015, Powell et al., 2009). In support, the pan-T-type calcium channel blocker, Z944, suppresses seizure activity in GAERS (Tringham et al., 2012). Further, Z944 administration not only suppresses seizure activity, but also improves cognitive deficits observed in GAERS, specifically, visual and crossmodal memory deficits (Marks et al., 2016a). Given the role of T-type calcium channels in GAERS neuropathology and the cognitive improvements observed in GAERS with Z944 treatment, examining the effect of Z944 on social behaviour in GAERS is warranted. The objective of this study was to examine dose-dependent effects of Z944 on sociability in GAERS and NEC rats using a three chambered sociability task (Millan and Bales, 2013, Nadler et al., 2004). Social interaction in this task is measured by preference to explore a cage containing a stranger rat as opposed to an empty cage. This sociability task is ideal in that social interaction is initiated by the test animal and placement of the stranger animal in a wire cage ensures aggressive behaviours between animals is limited (Crawley, 2007). The work demonstrated sociability deficits in GAERS animals. Further, sociability deficits in GAERS were reversed by Z944 administration.