mTOR inhibitor improves autistic-like behaviors related to Tsc2 haploinsufficiency 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 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), 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). Results Both 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). Conclusions These 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.

Extension of microglial activation is associated with epilepsy and cognitive dysfunction in Tuberous sclerosis complex: A TSPO-PET study

“…In a human clinical trial, although mTOR-i showed a favorable trend of ASD symptoms ( Mizuguchi et al, 2019 ), evidence for cognition and psychiatric comorbidity improvement with mTOR-i is lacking. Petrasek et al ( Petrasek et al, 2021 ) proposed a likely explanation that mTOR-i could improve the social deficit induced by TSC2 haploinsufficiency but not the deficits associated with developmental status epilepticus. In this study, although mTOR-i significantly reduced the severity of epilepsy and extension of microglial activation, the volume ratio DPA713/ICV did not correlate with GASE and IQ/DQ.…”

mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder

“…PTEN and TSC1/2 are upstream negative regulators of mTOR, mutations of them can also lead to the hyperactivity of the mTOR pathway and are associated with a high risk of ASD ( 20 , 36 , 41 ). Everolimus, an mTOR inhibitor, has shown the ability to reverse social behavior deficits in TSC2 mice without an additional epilepsy model ( 42 ). Hence, Trifonova et al.…”

The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model

“…Firstly, studies show that ASD is strongly associated to TSC and the heterozygous deletion of Tsc1 or Tsc2 considerably increase the individual’s risk for ASD development [ 146 ]. Patients with mutations of Tsc1 or Tsc2 , upstream repressors of mTOR activities, exhibit an array of autistic features that resemble idiopathic autism [ 147 ]. The subjects with TSC have reported to show a 100-fold increase in the susceptibility of getting diagnosed with autism in comparison to the normal individuals.…”