Tuberous Sclerosis (tsc2+/-) Model Eker Rats Reveals Extensive Neuronal Loss with Microglial Invasion and Vascular Remodeling Related to Brain Neoplasia

et al. 2021

Preprint

Self Cite

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), 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 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 in clinical studies not reliably ameliorated by mTOR inhibitors.

“…Epileptiform patterns seen in the Tsc2+/rat argue for the former, as the brains of Tsc2+/rats are virtually tumor-free until advanced age [43].…”

Section: Discussionmentioning

confidence: 94%

“…Sizes of experimental groups were calculated based on our data and experience from previous studies with the model [37][38][39][40]43]. Group sizes were also in uenced by the limited number of litters available from the mutant breeding line.…”

Section: Group Design and Timing Of Proceduresmentioning

confidence: 99%

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

Petrásek¹,

Vojtěchová²,

et al. 2021

Preprint

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“…In clinical contexts, it remains unclear whether epilepsy in TSC patients is attributable to the Tsc2+/mutation, is secondary to cortical tubers acting as epileptogenic foci [5] or may be a combination of both. Epileptiform patterns seen in the Tsc2+/rat argue for the former, as the brains of Tsc2+/rats are virtually tumor-free until advanced age [62].…”

Section: Discussionmentioning

confidence: 94%

“…Finally, we acknowledge the limitations of any translational research and the challenges to recapitulate mutational and behavioral equivalence between human and rodent models (62). However, we used an established heterozygous animal model of TSC, and used established paradigms of epilepsy and social behaviors, as used in pre-clinical research [67].…”

Section: Discussionmentioning

confidence: 99%

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

Petrásek¹,

Vojtěchová²,

et al. 2020

Preprint

Self Cite

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.

“…Sizes of experimental groups were calculated based on our data and experience from previous studies with the model [ 37 – 40 , 43 ]. Group sizes were also influenced by the limited number of litters available from the mutant breeding line.…”

Section: Methodsmentioning

confidence: 99%

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

Petrásek

Vojtěchová

et al. 2021

J Neurodevelop Disord

Self Cite

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.