Abstracts

Rationale: Approximately 1% of children have been diagnosed with Autism Spectrum Disorder. In addition approximately 1% of the US population is diagnosed with epilepsy and 1 in 10 individuals will have a seizure within their lifetime. Research has shown that there is high comorbidity between autism and epilepsy. However, the mechanism that results in this comorbidity is not well understood. Here, we evaluated the effects of superimposing seizures on a genetic mutation (NS-Pten heterozygous mice) that has been shown to be involved in autism and in epilepsy. We then measured their activity levels, anxiety, social behavior, repetitive behavior, and learning in a battery of behavioral tests. Methods: Multiple cohorts of NS-Pten heterozygous (HT) and wild-type (WT) adult mice received either injections of kainic acid (20 mg/kg; intraperitoneal) to induce status epilepticus (continuous seizures) or received the vehicle (saline). They received pentobarbital (20 mg/kg intraperitoneal) to terminate seizures one hour after the first injection. After a few days to recover they were examined through a battery of behavioral tests. We first tested the animals in the open field and elevated plus maze to determine activity levels and anxiety levels. We examined repetitive behavior though marble burying; examined social behavior using the social chamber test; examined their learning and memory through the Morris water maze and trace fear conditioning. Results: We found no difference to onset of the first seizure, onset to status epilepticus, or differences in mortality between the groups after kainate injection. We found that the NS-Pten HT seizure mice showed significant increase in activity in the open field (p < 0.05) compare to NS-Pten HT mice without seizures and WT controls. There were no differences in the time and frequency to visit the arms in the elevated plus maze or in the number of marbles buried in the marble burying test. The NS-PTEN HT seizure mice did perform more rearing events in the closed-arm of the elevated plus maze, p < 0.05. In the social chamber test, both the WT mice and NS-Pten heterozygous mice with seizures had a decrease in social interaction in the social chamber test. WT mice with seizures had a deficit in the probe test of MWM test. However, the NS-PTEN HT mice with seizures had no deficits in the probe test. The NS-PTEN HT mice with seizures displayed enhanced learning in trace fear conditioning compared to controls, p < 0.05 Conclusions: These findings demonstrate that superimposing a seizure on a genetic mutation can result in some long term alterations in activity and social behavior in mice. However, the haploinsufficient mice were protected against the learning deficits that occur with seizures. Future studies will help to examine the interaction of seizures and genetics.