A Mouse Model of Tuberous Sclerosis: Neuronal Loss of Tsc1 Causes Dysplastic and Ectopic Neurons, Reduced Myelination, Seizure Activity, and Limited Survival

Meikle, Lynsey M.; Talos, Delia M.; Onda, Hiroaki; Pollizzi, Kristen; Rotenberg, Alexander; Şahin, Mustafa; Jensen, Frances E.; Kwiatkowski, David J.

doi:10.1523/jneurosci.5540-06.2007

Cited by 409 publications

(481 citation statements)

References 69 publications

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“…Some neurons are ectopic in multiple sites in the cortex and hippocampus. This model replicates several neuropathological features of human TSC brain lesions [113].…”

Section: Tuberous Sclerosis Complexsupporting

confidence: 65%

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Novel Animal Models of Pediatric Epilepsy

et al. 2012

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When mimicking epileptic processes in a laboratory setting, it is important to understand the differences between experimental models of seizures and epilepsy. Because human epilepsy is defined by the appearance of multiple spontaneous recurrent seizures, the induction of a single acute seizure without recurrence does not constitute an adequate epilepsy model. Animal models of epilepsy might be useful for various tasks. They allow for the investigation of pathophysiological mechanisms of the disease, the evaluation, or the development of new antiepileptic treatments, and the study of the consequences of recurrent seizures and neurological and psychiatric comorbidities. Although clinical relevance is always an issue, the development of models of pediatric epilepsies is particularly challenging due to the existence of several key differences in the dynamics of human and rodent brain maturation. Another important consideration in modeling pediatric epilepsy is that "children are not little adults," and therefore a mere application of models of adult epilepsies to the immature specimens is irrelevant. Herein, we review the models of pediatric epilepsy. First, we illustrate the differences between models of pediatric epilepsy and models of the adulthood consequences of a precipitating insult in early life. Next, we focus on new animal models of specific forms of epilepsies that occur in the developing brain. We conclude by emphasizing the deficiencies in the existing animal models and the need for several new models.

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“…Some neurons are ectopic in multiple sites in the cortex and hippocampus. This model replicates several neuropathological features of human TSC brain lesions [113].…”

Section: Tuberous Sclerosis Complexsupporting

confidence: 65%

“…TSC1 synapsin CKO mice exhibit neuronal hyperexcitability and spontaneous seizures [112,113]. The TSC1 synapsin CKO mice have several neurological abnormalities, such as enlarged and/or dysplastic cortical and hippocampal neurons.…”

Section: Tuberous Sclerosis Complexmentioning

confidence: 99%

Novel Animal Models of Pediatric Epilepsy

et al. 2012

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“…Loss-of-function variants in negative regulators of mTORC1 signaling are the cause of several monogenic syndromes associated with intellectual disability and autism spectrum phenotypes, such as Fragile X syndrome, 9,29 tuberous sclerosis, 30 and PTEN-related syndromes. 31 In addition, overactivated mTORC1 signaling has also been linked to the pathophysiology of non-syndromic ASD.…”

Section: Discussionmentioning

confidence: 99%

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

et al. 2015

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Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuronspecific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.

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“…217 In mouse models of tuberous sclerosis, the conditional loss of Tsc1 leads to abnormal dendritic spine morphology and density, 218 enhanced cortical excitability, 219 enlarged neurons in the cortex and hippocampus, and seizures. 220 The altered excitation state of cortex in the Tsc1 conditional null mouse is not associated with tuber formation or changes in distribution of GAD67, used as a marker for GABAergic function. 219 The PI3K pathway is antagonized by PTEN, but can be stimulated by glutamate, 221 serotonin 222 and dopamine.…”

Section: The Conditional Pten-null Mousementioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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A Mouse Model of Tuberous Sclerosis: Neuronal Loss of Tsc1 Causes Dysplastic and Ectopic Neurons, Reduced Myelination, Seizure Activity, and Limited Survival

Abstract: Tuberous sclerosis (TSC) is a hamartoma syndrome caused by mutations in

Cited by 409 publications

References 69 publications

Novel Animal Models of Pediatric Epilepsy

Novel Animal Models of Pediatric Epilepsy

Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism

Advances in behavioral genetics: mouse models of autism

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