Epilepsy and Tsc2 Haploinsufficiency Lead to Autistic-Like Social Deficit Behaviors in Rats

Abstract

There is a strong association between autism spectrum disorders (ASD), epilepsy and intellectual disability in humans, but the nature of these correlations is unclear. The monogenic disorder Tuberous Sclerosis Complex (TSC) has high rates of ASD, epilepsy and cognitive deficits. Here we used the Tsc2 (+/-) (Eker) rat model of TSC and an experimental epilepsy paradigm to study the causal effect of seizures on learning and memory and social behavior phenotypes. Status epilepticus was induced by kainic acid injection at P7 and P14 in wild-type and Tsc2 (+/-) rats. At the age of 3-6months, adult rats were assessed in the open field, light/dark box, fear conditioning, Morris water maze, novel object recognition and social interaction tasks. Learning and memory was unimpaired in naïve Tsc2 (+/-) rats, and experimental epilepsy did not impair any aspects of learning and memory in either wild-type or Tsc2 (+/-) rats. In contrast, rearing in the open field, novel object exploration and social exploration was reduced in naïve Tsc2 (+/-) rats. Seizures induced anxiety and social evade, and reduced social exploration and social contact behavior in wild-type and Tsc2 (+/-) rats. Our study shows that Tsc2 haploinsufficiency and developmental status epilepticus in wild-type and Tsc2 (+/-) rats independently lead to autistic-like social deficit behaviors. The results suggest that the gene mutation may be sufficient to lead to some social deficits, and that seizures have a direct and additive effect to increase the likelihood and range of autistic-like behaviors.