Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice

McMahon, John J.; Yu, Wilson; Yang, Jun; Feng, Huiyun; Helm, Meghan; McMahon, Elizabeth; Zhu, Xingen; Shin, Damian S.; Huang, Yunfei

doi:10.1016/j.nbd.2014.10.004

Cited by 20 publications

(18 citation statements)

References 58 publications

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“…Previous studies showed that Tsc1 deletion in different cell types can result in epilepsy, for example, local Tsc1 deletion in CAMK2A‐expressing neurons, or Tsc1 deletion specifically in glial cells . Although these models are of great value, they are not very suitable to study the process of TSC/mTOR‐associated epileptogenesis as seizure onset is unpredictable and poorly controlled.…”

Section: Discussionmentioning

confidence: 99%

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Koene

Grondelle

Onori

et al. 2019

Ann Clin Transl Neurol

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Objective An epilepsy mouse model for Tuberous Sclerosis Complex (TSC) was developed and validated to investigate the mechanisms underlying epileptogenesis. Furthermore, the possible antiepileptogenic properties of commonly used antiepileptic drugs (AEDs) and new compounds were assessed. Methods Tsc1 deletion was induced in CAMK2A‐expressing neurons of adult mice. The antiepileptogenic properties of commonly used AEDs and inhibitors of the mTOR pathways were assessed by EEG recordings and by molecular read outs. Results Mice developed epilepsy in a narrow time window (10 ± 2 days) upon Tsc1 gene deletion. Seizure frequency but not duration increased over time. Seizures were lethal within 18 days, were unpredictable, and did not correlate to seizure onset, length or frequency, reminiscent of sudden unexpected death in epilepsy (SUDEP). Tsc1 gene deletion resulted in a strong activation of the mTORC1 pathway, and both epileptogenesis and lethality could be entirely prevented by RHEB1 gene deletion or rapamycin treatment. However, other inhibitors of the mTOR pathway such as AZD8055 and PF4708671 were ineffective. Except for ketogenic diet, none of commonly used AEDs showed an effect on mTORC1 activity. Vigabatrin and ketogenic diet treatment were able to significantly delay seizure onset. In contrast, survival was shortened by lamotrigine. Interpretation This novel Tsc1 mouse model is highly suitable to assess the efficacy of antiepileptic and ‐epileptogenic drugs to treat mTORC1‐dependent epilepsy. Additionally, it allows us to study the mechanisms underlying mTORC1‐mediated epileptogenesis and SUDEP. We found that early treatment with vigabatrin was not able to prevent epilepsy, but significantly delayed seizure onset.

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Section: Discussionmentioning

confidence: 99%

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Koene

Grondelle

Onori

et al. 2019

Ann Clin Transl Neurol

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“…Treatment with rapamycin in animals with neonatal hypoxic seizures was protective against the development of epilepsy and decreased the social novelty deficit. Another mouse model with conditional knockout of Tsc1 in forebrain neurons (under CaMKIIα-cre) further links mTOR hyperactivation with seizures and autism-like behaviors [73]. Decreased social behavior (in the 3-chamber social approach) and increased repetitive behaviors (marble burying) were observed in these mutant mice.…”

Section: Therapeutic Effects Of Mtor Inhibitor Treatment In Animal Momentioning

confidence: 98%

Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism

et al. 2015

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Tuberous sclerosis complex (TSC) is a genetic disorder with a high prevalence of autism spectrum disorder (ASD). Tremendous progress in understanding the pathogenesis of TSC has been made in recent years, along with initial trials of medical treatment aimed specifically at the underlying mechanism of the disorder. At the cellular level, loss of TSC1 or TSC2 results in upregulation of the mechanistic target of rapamycin (mTOR) pathway. At the circuitry level, TSC and mTOR play crucial roles in axonal, dendritic, and synaptic development and function. In this review, we discuss the molecular mechanism underlying TSC, and how this disease results in aberrant neural connectivity at multiple levels in the central nervous system, leading to ASD symptoms. We then review recent advances in mechanism-based treatments of TSC, and the promise that these treatments provide for future mechanism-based treatment of ASD. Because of these recent advances, TSC represents an ideal model for how to make progress in understanding and treating the mechanisms that underlie ASD in general.

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“…Moreover, loss of hamartin in the cerebral cortex and hippocampus leads to dysplastic neurons, ectopic neurons and reduced myelination, whereas astrocyte-specific deletion of Tsc1 initiates astrogliosis and the aberrant migration of hippocampal pyramidal neurons ( Meikle et al, 2007 ; Uhlmann et al, 2002 ). Such changes to CNS architecture subsequently lead to functional and autistic-like behavioural deficits ( McMahon et al, 2014 ; Meikle et al, 2007 ; Reith et al, 2013 ; Tavazoie et al, 2005 ; Tsai et al, 2012 ; Uhlmann et al, 2002 ). However, although these previous conditional ablation studies have generated substantial insight into the neurological and behavioural aspects of TSC, it is still imperative to generate innovative models that specifically address the roles of hamartin and tuberin in other TSC-affected organs.…”

Section: Introductionmentioning

confidence: 99%

A novel mouse model of Tuberous Sclerosis Complex (TSC): eye-specific Tsc1-ablation disrupts visual pathway development

Jones

Hägglund

Törnqvist

et al. 2015

Disease Models &Amp; Mechanisms

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Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that is best characterised by neurodevelopmental deficits and the presence of benign tumours (called hamartomas) in affected organs. This multi-organ disorder results from inactivating point mutations in either the TSC1 or the TSC2 genes and consequent activation of the canonical mammalian target of rapamycin complex 1 signalling (mTORC1) pathway. Because lesions to the eye are central to TSC diagnosis, we report here the generation and characterisation of the first eye-specific TSC mouse model. We demonstrate that conditional ablation of Tsc1 in eye-committed progenitor cells leads to the accelerated differentiation and subsequent ectopic radial migration of retinal ganglion cells. This results in an increase in retinal ganglion cell apoptosis and consequent regionalised axonal loss within the optic nerve and topographical changes to the contra- and ipsilateral input within the dorsal lateral geniculate nucleus. Eyes from adult mice exhibit aberrant retinal architecture and display all the classic neuropathological hallmarks of TSC, including an increase in organ and cell size, ring heterotopias, hamartomas with retinal detachment, and lamination defects. Our results provide the first major insight into the molecular etiology of TSC within the developing eye and demonstrate a pivotal role for Tsc1 in regulating various aspects of visual-pathway development. Our novel mouse model therefore provides a valuable resource for future studies concerning the molecular mechanisms underlying TSC and also as a platform to evaluate new therapeutic approaches for the treatment of this multi-organ disorder.

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Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice

Cited by 20 publications

References 58 publications

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Effects of antiepileptic drugs in a new TSC/mTOR‐dependent epilepsy mouse model

Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism

A novel mouse model of Tuberous Sclerosis Complex (TSC): eye-specific Tsc1-ablation disrupts visual pathway development

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