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 3-6 months, 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.

mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus

“…2). In Tsc2 +/− (Eker)-rats plus DSE, locomotor activity was reduced, seen as a trend in our previous study [18]. Developmental delay in locomotor skills is frequently observed in neurodevelopmental disorders [25].…”

“…This social deficit in adult rats was accelerated by the previous experience of DSE induced during early childhood in these Tsc2 +/− (Eker)-rats [16][17][18]. Given that patients with ASD in TSC often have a history of previous developmental epilepsy, the P7 and P14 DSE scenario in Tsc2 +/− (Eker)-rats suggests an animal model of impaired social behaviour, closer to the situation of TSC patients than those caused by a Tsc1 or Tsc2 mutation alone.…”

“…In a previous study, we described a phenotype of impaired social interaction in Tsc2 +/− (Eker)-rats with additive social deficits contributed by DSE [18]. The analysis of social interaction repeated here, between the test animal and a social partner, included anogenital and non-anogenital exploration as well as approach and following behaviour.…”

From Molecules to Behavior: Lessons from the Study of Rare Genetic Disorders

“…Another example of how studies of rare diseases may pave the way for understanding more common ones comes from the study of Waltereit and colleagues in this issue (Waltereit et al 2011). They used a naturally occurring TSC2 rat, the Eker rat, to examine the relationship between seizures and autism.…”

Os produtos dos genes Tsc1 e Tsc2 em processos neurodegenerativos

“…Entretanto, nas regiões corticais e subcorticais do cérebro, as lesões decorrentes de falhas de migração neuronal e sua arborização podem ser explicadas pela haploinsuficiência de TSC1 ou TSC2 (GOORDEN et al, 2007;WALTEREIT et al, 2011). Estas apresentamse comumente com epilepsia refratária (aproximadamente 60% dos casos), a qual, por sua vez, pode se associar a deficiência intelectual (50% do total de casos) e transtornos do espectro autista (40 a 50%) ou de hiperatividade e déficit de atenção (30 a 50%) (CURATOLO et al, 2015).…”