mTOR Inhibitor Reverses Autistic-like Behaviour in Tsc2+/- Rats with Developmental Epilepsy

Background: Developmental epilepsy is a major risk factor for autism spectrum disorder (ASD) and complicates clinical manifestations and management of ASD significantly. Tuberous Sclerosis Complex (TSC), caused by TSC1 or TSC2 mutations, is one of the medical conditions most commonly associated with ASD and has become an important model to examine molecular pathways associated with ASD. Previous research showed reversal of autism-like social deficits in Tsc1+/- and Tsc2+/- mouse models by mammalian Target of Rapamycin (mTOR) inhibitors. However, at least 70% of individuals with TSC also have epilepsy, known to complicate the severity and treatment-responsiveness of the behavioural phenotype. Tsc2+/- (Eker)-rats express autism-like social deficits similar to Tsc2+/- mice, with additive social deficits from status epilepticus during development.

Objectives: Here we hypothesised that the mTOR inhibitor everolimus would exert beneficial effects on social interaction and cognition in Tsc2+/- (Eker)-rats with previously induced developmental epilepsy.

Methods: The experimental group that modelled TSC pathology carried the Tsc2+/- (Eker)-mutation and was challenged with pharmacologically induced status epilepticus at postnatal days (P) 7 and P14 (n=12). The control group consisted of wild-type carriers from the Eker rat line and did not receive developmental epilepsy (n=10). At the age of four months, all animals were investigated in the pre-treatment behavioural analysis (T1). They were then treated for one week every other day with 1 mg/kg everolimus per bodyweight by intraperitoneal injection. Finally, they were retested in the post-treatment behavioural analysis (T2).

Results: Everolimus successfully treated the social interaction and social cognitive deficits in Tsc2+/- (Eker)-rats with status epilepticus induced during development. The drug was well tolerated and did not affect body weight. Non-social activity behaviour was not changed by everolimus. The mTOR-inhibitor specifically rescued the autistic-like phenotype of impaired social exploration behaviours. It also reversed the deficits in social recognition memory.

Conclusions: Our findings suggest that mTOR-inhibitors may be a potential treatment of autistic-like behaviours not only associated with a TSC mutation but also of social deficits associated with epilepsy in TSC. Results suggest that mTOR inhibitors may therefore be a potential treatment also of social deficits associated with other seizure-related disorders.