mTOR inhibitor Treats Autistic-like Behaviors in Tsc2+/- rats but not following Developmental Status Epilepticus

Abstract

Background: Tuberous Sclerosis Complex (TSC), a multi-system genetic disorder often associated with Autism Spectrum Disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian Target of Rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not yet shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC, but absent in most animal models, could explain the discrepancy. Methods: At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze and novel object recognition. Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). The testing was carried out before medication (T1), during treatment with the mTOR inhibitor everolimus (T2) and after washing-out (T3). Results: Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). Conclusions: These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were so far in clinical studies not reliably ameliorated by mTOR inhibitors.