Abstract
Epilepsy is a significant contributor to worldwide disability. In epilepsy, disability can be broadly divided into 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 aspects of ictal and interictal behavior in mice using instrumented home-cage chambers designed to assay kinematic and appetitive behavioral measures. Through daily intraperitoneal injections of the chemoconvulsant pentylenetetrazole (PTZ) applied to C57BL/6J mice, we coordinately measure how “behavioral severity” (complex dynamic changes in movement and sheltering behavior) and convulsive severity (latency and occurrence of convulsive seizures) evolve or kindle with repeated injections. By closely studying long epochs between PTZ injections, we identify an interictal syndrome of nocturnal hypoactivity and increased sheltering behavior which remits with the cessation of seizure induction. 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 the overall severity of a PTZ-induced seizure. 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.
Highlights
Epilepsy, or the epilepsies, are an etiologically diverse group of disorders defined by an enduring predisposition to develop epileptic seizures, and by associated neurobiologic, cognitive/ psychological and social consequences [1]
Since the behavioral expression of a static epileptogenic lesion may depend upon the timing of the most recent seizure, we submit that home-cage behavioral monitoring is well suited to study the dynamics of interictal behavior in mouse models of epilepsy
As we continue to expand our knowledge of epilepsy genetics, innovate mouse models that recapitulate those genetic lesions, and apply novel anatomically targeted methods to interrogate network dysfunction in epilepsy, we must continue to refine our assessment of seizure severity and interictal behavior in preclinical models
Summary
The epilepsies, are an etiologically diverse group of disorders defined by an enduring predisposition to develop epileptic seizures, and by associated neurobiologic, cognitive/ psychological and social consequences [1]. In studies of adults with epilepsy, selfreported disability assessments show some correlation to seizure frequency/recency, and correlate with anticonvulsant side effects and the intensity of comorbid mental health
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