Elsevier

Experimental Neurology

Volume 256, June 2014, Pages 74-80
Experimental Neurology

Early-life seizures result in deficits in social behavior and learning

https://doi.org/10.1016/j.expneurol.2014.03.014Get rights and content

Highlights

  • We induced seizures during early development in mice.

  • Early-life seizures result in social behavior deficits.

  • Early-life seizures result in learning and memory deficits.

  • Early-life seizures did not produce alterations in repetitive behaviors.

Abstract

Children with epilepsy show a high co-morbidity 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. In order to examine whether seizures during postnatal days 7–11 result in learning and memory deficits and behavioral features of autism we administered the inhalant flurothyl to induce seizures in C57BL/6J mice. Mice received three seizures per day for five days starting on postnatal day 7. Parallel control groups consisted of similarly handled animals that were not exposed to flurothyl and naïve mice. Subjects were then processed through a battery of behavioral tests in adulthood: elevated-plus maze, nose-poke assay, marble burying, social partition, social chamber, fear conditioning, and Morris water maze. Mice with early-life seizures had learning and memory deficits in the training portion of the Morris water maze (p < 0.05) and probe trial (p < 0.01). Mice with seizures showed no differences in marble burying, the nose-poke assay, or elevated plus-maze testing compared to controls. However, they showed a significant difference in the social chamber and social partition tests. Mice with seizures during postnatal days 7–11 showed a significant decrease in social interaction in the social chamber test and had a significant impairment in social behavior in the social partition test. Together, these results indicate that early life seizures result in deficits in hippocampal-dependent memory tasks and produce long-term disruptions in social behavior.

Introduction

The relationship between epilepsy and autism has been discussed for over 5 decades (Creak and Pampiglione, 1969, Schain and Yannet, 1960). Epidemiological studies suggest that perhaps as many as 25% of individuals with autism have some form of epilepsy (Tuchman and Rapin, 2002). However, the reported rates of epilepsy in autism vary between 5 and 40% (Canitano, 2007). This large range is likely attributed to the heterogeneity of the patient populations in individual studies. There are several risk factors that increase the probability of comorbidity of epilepsy and autism. Children who have a seizure in the first year of life have a higher risk for autism than those in the general population (Saemundsen et al., 2007). In addition, seizures are more frequently found in individuals with autism and intellectual disability. Even though there is an elevated risk of epilepsy in individuals with autism and intellectual disability, it is not clear whether seizures directly influence the development of autistic features and cognitive dysfunction.

Studies in animal models could help elucidate the potential interplay between these comorbidities. For instance, normal animals without neuropathology can be induced to have seizures to determine if seizures themselves contribute to autistic and cognitive disabilities. Indeed, resultes from numerous laboratories have reported that early-life seizures result in learning and memory deficits. Rats that experience brief but recurrent seizures during the first weeks of postnatal life have visual and auditory spatial learning and memory deficits during later adolescence and adulthood (Holmes et al., 1998, Neill et al., 1996). In addition, rats that experience seizures during early development show defective hippocampal place cells involved in spatial learning (Karnam et al., 2009).

Even though there is significant evidence that early-life seizures result in learning and memory deficits in later life, the influence of seizures on autistic-like behaviors such as social and repetitive behaviors has received less attention. In the experiments reported here, we examined whether flurothyl-induced seizures during postnatal days 7–11 affect social and repetitive behaviors and learning and memory deficits. Given the comorbidity between epilepsy and autism and the background studies presented above, we hypothesized that early-life seizures would lead to impairments in autistic-like behaviors and learning and memory.

Section snippets

Animals

Starting on postnatal day 7, mice were placed in an acrylic container located in an exhaust hood. A gauze located in the chamber but above the pups received a flurothyl (bis-2,2,2-trifluoroethyl ether, Aldrich Chemical Co., USA) solution that was infused into the chamber at a rate of 3 cm3/h through a Hamilton syringe pump. Flurothyl was administered until all the mice displayed tonic extension of forelimbs and hindlimbs. The animals were then removed from the chamber and allowed to recover

Data analysis

All data were analyzed by using SPSS 17.0 for PC (SPSS, Chicago, IL). For all comparisons, the level of significance was set at p < 0.05. For all analyses naïve controls and handled controls were combined since no statistically significant differences were found between the groups. Males and females were also combined per group since no statistically significant differences were found between them. Animals were monitored for normal weight gain and no significant differences were found between

To determine if early-life seizures lead to deficits in social behavior we used the social partition and social chamber tests

Mice that underwent seizures during postnatal days 7–11 displayed a significant decrease in social behavior in the social partition test compared to control animals [F(1,29) = 6.627, p < 0.05]. We found a significant interaction between group and testing conditions [F(2,58) = 14.75, p < 0.001], and thus we used repeated-measures ANOVAs to analyze the groups separately over the three conditions. The control group showed the expected pattern of social interaction for a normal rodent. There was some

Discussion

Individuals with autism show behavioral abnormalities in three core areas: social, stereotypic/repetitive, and communication. There is a high comorbidity with autism and cognitive impairment as well as seizures and epilepsy. In these situations it is unclear whether seizures themselves contribute to the autistic phenotype and cognitive impairments. In the present study we demonstrate that mice that experience brief seizures during postnatal days 7–11 have a significant reduction in social

Conclusions

Our work demonstrates that flurothyl seizures induced in mice on postnatal days 7–11 result in long-term deficits in social behavior and spatial learning and memory. Our results provide evidence that seizures during early-life produce behavioral deficits in social behavior. These alterations are specific to one of the three core features of autism, since there was no difference in repetitive behaviors.

Acknowledgments

This research was funded by the Epilepsy Foundation (221523) and NIH NS056664 Postdoctoral Fellowships to JNL, NIH NINDS grants NS049427 and NS039943 to AEA, and NIH NINDS grant NS018309 to JWS. The work was completed at the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (IDDRC) Mouse Neurobehavior Core, which receives funding from the NIH P30HD 024064 from the Eunice Kennedy Shriver Institute of Child Health and Human Development. The content is solely

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    In addition, there was no significant effect of seizure administration (F[1,32] = 0.81, p = 0.37), treatment (F[3,32] = 0.51, p = 0.68), or an interaction (F[3,32] = 0.59, p = 0.62) for GFAP expression levels in female mice (Fig. 10D). Early-life seizures can have profound effects on the developing brain and have been associated with both acute and long-term impairments in cognition and behavior [15,34,35]. Hyperactivity of the mTOR pathway and neuroinflammation contribute to epileptogenesis and could serve as promising therapeutic targets for epilepsy.

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