Abstracts

Rationale: Children with epilepsy show a high comorbidity with psychiatric disorders and autism. One of the critical determinants of a child's behavioral outcome with autism and cognitive dysfunction is the age of onset of seizures. The aim of this study was to investigate whether early-onset epilepsy triggered with status epilepticus (SE) in infantile rats leads to deficits in specific behavioral dimensions including cognitive functions, alterations in emotionality and social functioning later in life. Methods: SE was induced with pilocarpine (35 mg/kg i.p.) in P12 rats pretreated with LiCl (127 mg/kg) 24 hr earlier. After 1.5 hr of convulsive seizures, animals received paraldehyde (0.07 mg/kg). Controls received saline instead of pilocarpine. Animals were repeatedly tested at different stages of maturation in order to examine whether SE affects: (1) non-associative memory expressed as habituation of exploratory behavior in the open-field test and investigatory response to a stimulus object (2) sociability/social novelty preference (3) social recognition or discrimination; and (4) short- and long-term memory in the Morris water maze (MWM). In parallel, severity of acute damage and its distribution across brain structures that are critically involved in neural circuitry underlying these behavioral paradigms was studied with FluoroJade B in additional groups of animals. Results: Early SE did not affect habituation in the open field (OF) test and its development. Time spent in the central part of the OF arena was significantly shorter in SE animals indicating higher anxiety in this group. In addition, adult animals with early SE spent significantly less time investigating a stimulus object that suggests attention deficits. At all ages the SE rats demonstrated a marked deficit in sociability and preference for social novelty. Both control and SE animals learned to reach the platform in Morris water maze test, however, SE animals used a different search strategy. No differences between controls and SE animals were observed in the probe trials at either interval of testing suggesting spared memory retention. Neuropathological analysis of FJB-stained sections obtained 24hr after SE revealed degenerating neurons in the hippocampus, perirhinal cortex, mediodorsal nucleus of the thalamus, and amygdala. Conclusions: Our findings indicate that early life SE leads to anxiety-related behavior, emotional and attention deficit, and affects sociocognitive memory processing, expressed by a low preference for social novelty and social discrimination. Acutely, SE produces damage to the neural circuitry, that is playing a critical role in acquisition, storage and retrieval of various memory processes, programming of social behavior and mediation of behaviors with motivation/incentive and affective properties. Funding: Study was supported by grant 16-04726S of the Czech Science Foundation, project PHARMABRAIN, reg. no. CZ.02.1.01/0.0/0.0/16_025/0007444 (co-supported by EU) and Research Project RVO 67985823.