MTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency but not following developmental status epilepticus

Tomas Petrasek,Jakub Rak,Nadine Bernhardt,Jakub Otahal,Klara Tuckova,Daniel Kaping,Robert Waltereit,Iveta Vojtechova,Anna Sulakova,Cestmir Vejmola,Ondrej Klovrza,Petrus J De Vries

doi:10.1186/s11689-021-09357-2

Abstract

BackgroundTuberous 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 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.MethodsAt 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), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18).ResultsBoth Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3).ConclusionsThese findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

Highlights

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
Severity of pilocarpine-induced developmental status epilepticus (DSE) is independent of pup genotype Pilocarpine injection at P12 caused diarrhea and seizures accompanied by automatic scratching, drumming motions, tremors, limb extensions, postural problems, and wild running, which is consistent with signs described in the literature [58]
Our study aimed to investigate whether early epileptic seizure has an additional effect on the ASD-like phenotype in an animal model with Tsc2 haploinsufficiency, and whether the Tsc2+/- and seizure-induced behavioral deficits differ in their responsivity to mTOR inhibitors (mTORi) treatment

Summary

Introduction

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. Phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with an incidence of 1:6000, with manifestations (including, but not limited to, benign tumors and other types of lesions) that can affect almost every organ in the body, including the brain. TSC is associated with ASD in up to 50% of individuals, and in turn, accounts for 1–4% of overall autism cases [6,7,8]. A lifetime history of epilepsy is reported in 70–90% of individuals with the disorder [9,10,11,12,13,14]

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