Rhythm and blues: Animal models of epilepsy and depression comorbidity

Abstract

Clinical evidence shows a strong, bidirectional comorbidity between depression and epilepsy that is associated with decreased quality of life and responsivity to pharmacotherapies. At present, the neurobiological underpinnings of this comorbidity remain hazy. To complicate matters, anticonvulsant drugs can cause mood disturbances, while antidepressant drugs can lower seizure threshold, making it difficult to treat patients suffering from both depression and epilepsy. Animal models have been created to untangle the mechanisms behind the relationship between these disorders and to serve as screening tools for new therapies targeted to treat both simultaneously. These animal models are based on chemical interventions (e.g. pentylenetetrazol, kainic acid, pilocarpine), electrical stimulations (e.g. kindling, electroshock), and genetic/selective breeding paradigms (e.g. Genetically Epilepsy-Prone Rats (GEPRs), Genetic Absence Epilepsy Rat from Strasbourg (GAERS), WAG/Rij rats, Swim Lo-Active rats (SwLo)). Studies on these animal models point to some potential mechanisms that could explain epilepsy and depression comorbidity, such as various components of the dopaminergic, noradrenergic, serotonergic, and GABAergic systems, as well as key brain regions, like the amygdala and hippocampus. These models have also been used to screen possible therapies. The purpose of the present review is to highlight the importance of animal models in research on comorbid epilepsy and depression and to explore the contributions of these models to our understanding of the mechanisms and potential treatments for these disorders.

Animal models of epilepsy: use and limitations

“…Therefore, a battery of models is required during the development of AEDs. ES models have also been employed to examine modifications of intracellular cascades and/or posttranslational modifications of proteins to clarify how epileptiform activities relate to synaptic plasticity dysfunctions, cognitive deficits, and psychiatric comorbidities 50–52. For instance, Tsankova et al51 demonstrated that chromatin remodeling is involved in ES-induced regulation of c-fos and the brain-derived neurotrophic factor (BDNF).…”

Issues in Clinical Epileptology: A View from the Bench. a Festschrift in Honor of Philip A. Schwartzkroin, PhD

“…Depression is extremely common in patients with epilepsy, affecting up to 30% of individuals with epilepsy (20). The recent availability of animal models of depression opens avenues for exploring the neurobiological mechanisms of these overlapping disorders (21). For example, in the lithium-pilocarpine model of temporal lobe epilepsy, it has been proposed that activation of the interleukin-1β signaling pathway in the hippocampus leads to dysregulation of the hypothalamic-pituitary axis, upregulating serotonin receptors in brainstem regions such as the raphe nucleus.…”

Single-Gene Determinants of Epilepsy Comorbidity

“…Substantial human and animal investigation has focused on the limbic system as a shared anatomical substrate for epilepsy and depression, but the models are primarily based on chemical interventions and suffer from the difficulty in equating motor behavior profiles with depression-like human symptomatology (Nestler and Hyman 2010;Epps and Weinshenker 2013). Imaging studies reveal an overlap in structural, hypometabolic, and serotonergic receptorbinding changes in limbic brain regions where chronic epilepsy patients show abnormalities, in particular, the left orbitofrontal and anterior cingulate cortex (Kanner et al 2012).…”