Elevated anxiety and depressive-like behavior in a rat model of genetic generalized epilepsy suggesting common causation

Abstract

The explanation for the increased prevalence of neuropsychiatric disorders in epilepsy patients is uncertain, with both biological and psychosocial factors proposed. Increasing evidence supports the idea of shared neurobiological processes leading both to seizures and to behavioral, emotional and cognitive disturbance. This study addresses this using Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of human generalized epilepsy.

We subjected GAERS (n = 47) and Non-Epileptic Control rats (NEC; n = 73) to behavioral measures of depression and anxiety at 7 and 13 weeks of age, ages prior to and after seizure onset. We employed the Sucrose-Preference Test (SPT), the Elevated Plus Maze (EPM), and the Open Field Arena (OFA).

GAERS exhibited significantly greater levels of both depression- and anxiety-like behaviors on all measures, including reduced consumption of sucrose solution in the SPT; lower percentage of time in the open arms of the EPM; and reduced exploratory activity and less time spent in the inner area of the OFA. These differences were evident at both 7 and 13 weeks of age, before and after the onset of epilepsy.

Increased anxiety- and depressive-like behaviors are observed in GAERS. These behavioral differences exist before the onset of seizures indicating that they are not secondary consequences of seizures, and suggest shared factors in the biological diathesis underlying the two kinds of disorder. Studying affective disturbance in animal models of epilepsy may illuminate the pathogenesis of affective disorder more generally, as well as modeling psychiatric comorbidities common in epilepsy patients.

Introduction

Animal models have been and continue to be an indispensable approach to researching the etiology and pathogenesis of psychiatric disorders (Charney and Nestler, 2004). An important variation on this theme is the study of behavioral, affective, and cognitive disturbance in animal models of neurological disorders. The study in humans of ‘organic’ psychiatric disorders, such as the depression accompanying stroke or Parkinson's disease, has shed light on ‘functional’ depression (Mayberg, 2001); similarly, the study of behavioral disturbance in animal models of neurological disorders has great potential value. To date the main neurological disorder in which affective disturbance has been studied in animal models is epilepsy.

Within biological psychiatry, probably the best known work emerging from epilepsy animal model research is the important contributions by Post and colleagues applying the concept of electrical kindling to affective disorder (Post, 2002); and of Adamec and colleagues exploring the connections between kindling and anxiety in cats and rodents (Adamec and Young, 2000). Less well appreciated is that several other animal models of various types of epilepsy – both genetic as well as acquired, and with generalized as well as focal seizures – have been found to exhibit apparent behavioral disturbances. These include Genetically Epilepsy-Prone Rats (GEPRs; Jobe and Browning, 2007), ‘FAST’ kindling rats (McIntyre et al., 2002), WAG-Rij rats (Sarkisova et al., 2003), and experimental febrile seizures (Mesquita et al., 2006).

Idiopathic generalized epilepsies (IGE) account for 15–20% of epilepsy cases (Jallon and Latour, 2005). The clinical data for psychiatric comorbidity in IGE are less extensive than for focal epilepsies (especially Temporal Lobe Epilepsy) but psychiatric disorders, largely anxiety and depressive disorders, have been estimated to affect up to 60% of IGE sufferers (Ott et al., 2003), representing a 3–6-fold increase in risk compared to the general population. However, the explanation for this increased rate of affective disturbance is currently not known, with both biological and psychosocial explanations possible. Behavioral disturbance may be a secondary consequence of seizure activity, due to chronic anti-epileptic medication, or an effect of the psychosocial challenges of suffering from a neurological disability. Another explanation for this coexistence is that shared neurodevelopmental, genetic, or environmental causes predispose subjects to develop both epilepsy and mental disorder.

GAERS (Genetic Absence Epilepsy Rats from Strasbourg) are a well-validated animal model of human IGE (Danober et al., 1998). With a few exceptions with respect to cognitive processing (Getova et al., 1997, Vergnes et al., 1991), the limited previous research performed on psychosocial behavior in GAERS has reported that they exhibit a behavioral phenotype – including locomotor and exploratory activity, aggressive behavior, and social interaction – indistinguishable from that of control rats (Marescaux et al., 1992, Vergnes et al., 1991). However, no formal assessments for affective behavioral disturbances in GAERS have been published, and the previous descriptions did not accord with our own informal observations in working with this strain: they seemed to be markedly more anxious during handling than other rat strains in our laboratory, including their non-epileptic counterparts. Similar observations have also been made by researchers working with the original GAERS colony in Strasbourg (A. Nehlig and D. Pinault, personal communication). Thus we designed this study to determine objectively whether GAERS and control rats exhibit differences in affective behavior, particularly focusing on features of a depressive and/or anxious phenotype. Furthermore, we aimed to clarify when such differences might emerge in relation to the onset of the seizure activity in order to address the question regarding the possible causative contribution of the seizures themselves.

Our studies demonstrated that GAERS do exhibit an increase in anxiety- and depressive-like behaviors compared to their non-epileptic control (NEC) counterparts. These behavioral differences exist before the onset of seizures indicating that they are not a secondary consequence of seizures. Most previous research on GAERS focuses on treatment and/or the pathophysiology and development of the seizures. However, our findings indicate that studies comparing GAERS and NEC rats may also provide a powerful model to investigate the neurobiological and genetic determinants of animal behavior and affective disturbance (Marescaux et al., 1992).