Epilepsy and its neurobehavioral comorbidities: Insights gained from animal models

It is well established that epilepsy is associated with numerous neurobehavioral comorbidities, with a bidirectional relationship; people with epilepsy have an increased incidence of depression, anxiety, learning and memory difficulties, and numerous other psychosocial challenges, and the occurrence of epilepsy is higher in individuals with those comorbidities. Although the cause-and-effect relationship is uncertain, a fuller understanding of the mechanisms of comorbidities within the epilepsies could lead to improved therapeutics. Here, we review recent data on epilepsy and its neurobehavioral comorbidities, discussing mainly rodent models, which have been studied most extensively, and emphasize that clinically relevant information can be gained from preclinical models. Furthermore, we explore the numerous potential factors that may confound the interpretation of emerging data from animal models, such as the specific seizure induction method (e.g., chemical, electrical, traumatic, genetic), the role of species and strain, environmental factors (e.g., laboratory environment, handling, epigenetics), and the behavioral assays that are chosen to evaluate the various aspects of neural behavior and cognition. Overall, the interplay between epilepsy and its neurobehavioral comorbidities is undoubtedly multifactorial, involving brain structural changes, network-level differences, molecular signaling abnormalities, and other factors. Animal models are well poised to help dissect the shared pathophysiological mechanisms, neurological sequelae, and biomarkers of epilepsy and its comorbidities.