Abstract

Epilepsy is a significant contributor to worldwide disability. In epilepsy, disability has two components: ictal (pertaining to the burden of unpredictable seizures and associated medical complications including death) and interictal (pertaining to more pervasive debilitating changes in cognitive and emotional behavior). In this study, we objectively and noninvasively appraise correlates of ictal and interictal disability in mice using instrumented home-cage chambers designed to assay kinematic and appetitive behavioral measures. We discover that in C57BL/6J mice, intraperitoneal injections of the chemoconvulsant pentylenetetrazole (PTZ) acutely result in complex and dynamic changes in movement and sheltering behavior that evolve (or kindle) with repeated daily injections, and which are separate from the occurrence of convulsions. By closely studying \"interictal\" periods (between PTZ injections), we identify a syndrome of nocturnal hypoactivity and increased sheltering behavior. We observe elements of this interictal behavioral syndrome in seizure-prone DBA/2J mice and in mice with a pathogenic Scn1a mutation (modeling Dravet syndrome). Through analyzing their responses to PTZ, we illustrate how convulsive severity and \"behavioral\" severity are distinct and independent aspects of overall seizure severity. Our results illustrate the utility of an ethologically centered automated approach to quantitatively appraise murine expressions of disability in mouse models of seizures and epilepsy. In doing so, this study highlights the very unique psychopharmacological profile of PTZ.\n\nSignificance StatementEpilepsy is a brain disorder characterized by a pervasively increased risk to develop epileptic seizures. Sadly, patients with epilepsy also experience high rates of anxiety, depression and other psychiatric symptoms that significantly increase overall disability. While many mouse models of seizures and epilepsy exist, we need improved techniques to measure how new treatments impact not only seizure occurrence, but also emotional changes that persist in between seizures. In this study, we apply the technique of home-cage monitoring to clarify precisely how spontaneous mouse behavior is altered in three distinct epilepsy models. Our work illustrates the importance of an ethologically centered appreciation of neuropsychiatric disability in mice and clarifies a new approach to the measurement of \"seizure severity\".