Cellular localization of metabotropic glutamate receptors in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex

Boer, Karin; Troost, Dirk; Timmermans, Wendy; Gorter, Jan A.; Spliet, Wim G.M.; Nellist, Mark; Jansen, Frank-Willem; Aronica, Eleonora

doi:10.1016/j.neuroscience.2008.06.073

Cited by 53 publications

(34 citation statements)

References 71 publications

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“…We did not explore other features such as K + channel and glutamate transporter expression that are altered in epileptic astrocytes or Tsc1 null astrocytes (36,(50)(51)(52). However, human tubers, which have variable degrees of gliosis, are removed from patients who undergo surgical treatment for focal epilepsy mapped to the resected tubers (53). It is unknown whether tubers not associated with seizures have gliosis (38).…”

Section: Discussionmentioning

confidence: 99%

Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice

Feliciano¹,

Su²,

López³

et al. 2011

J. Clin. Invest.

148

149

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Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by mutations in Tsc1 orTsc2 that lead to mammalian target of rapamycin (mTOR) hyperactivity. Patients with TSC suffer from intractable seizures resulting from cortical malformations known as tubers, but research into how these tubers form has been limited because of the lack of an animal model. To address this limitation, we used in utero electroporation to knock out Tsc1 in selected neuronal populations in mice heterozygous for a mutant Tsc1 allele that eliminates the Tsc1 gene product at a precise developmental time point. Knockout of Tsc1 in single cells led to increased mTOR activity and soma size in the affected neurons. The mice exhibited white matter heterotopic nodules and discrete cortical tuber-like lesions containing cytomegalic and multinucleated neurons with abnormal dendritic trees resembling giant cells. Cortical tubers in the mutant mice did not exhibit signs of gliosis. Furthermore, phospho-S6 immunoreactivity was not upregulated in Tsc1-null astrocytes despite a lower seizure threshold. Collectively, these data suggest that a double-hit strategy to eliminate Tsc1 in discrete neuronal populations generates TSC-associated cortical lesions, providing a model to uncover the mechanisms of lesion formation and cortical hyperexcitability. In addition, the absence of glial reactivity argues against a contribution of astrocytes to lesion-associated hyperexcitability.

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Section: Discussionmentioning

confidence: 99%

Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice

Feliciano¹,

Su²,

López³

et al. 2011

J. Clin. Invest.

148

149

View full text Add to dashboard Cite

show abstract

“…For example, large-scale gene expression studies indicate alterations in glutamatergic and GABAergic synaptic transmission in cortical tubers, involving reduced expression of the glial glutamate transporter (GLT-1 or EAAT2), reduced expression levels of GABA A receptor subunits, and reduced expression of potassium channels [135]. Selective alterations of iGlu subunits, as well as of mGluR subtypes (with prominent group I mGluR expression, mGluR1, and mGluR5) have been reported in tubers [193,223,224]. In addition (as discussed above) an excitatory action of GABA has been reported in TSC [162].…”

Section: Epileptogenesismentioning

confidence: 99%

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

Aronica

Crino

2014

Neurotherapeutics

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“…Various research teams have studied the expression of certain genes in cortical tubers resected from patients who underwent epilepsy surgery. In addition to abnormal expression of genes encoding GABA A receptor subunits and glutamate receptors [White et al, 2001;Boer et al, 2008b;Talos et al, 2008], also observed in other forms of drug-resistant epilepsy, the expression of genes associated with the immune system and the inflammatory response, such as those encoding cell adhesion molecules, complement factors, serpin A3, chemokine ligand 2 and several cytokines, was also shown to be increased in tubers, compared to control tissues [Boer et al, 2010]. This phenomenon was particularly noted in tubers where the mTOR cascade is highly activated, suggesting a direct effect of the latter on that specific gene activation [Boer et al, 2010].…”

Section: Epilepsy In Tuberous Sclerosis Complexmentioning

confidence: 99%

Seizures and Epilepsies due to Channelopathies and Neurotransmitter Receptor Dysfunction: A Parallel between Genetic and Immune Aspects

Lascano¹,

Korff

Picard³

2016

Mol Syndromol

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Despite intensive research activity leading to many important discoveries, the pathophysiological mechanisms underlying seizures and epilepsy remain poorly understood. An important number of specific gene defects have been related to various forms of epilepsies, and autoimmunity and epilepsy have been associated for a long time. Certain central nervous system proteins have been involved in epilepsy or acute neurological diseases with seizures either due to underlying gene defects or immune dysfunction. Here, we focus on 2 of them that have been the object of particular attention and in-depth research over the past years: the N-methyl-D-aspartate receptor and the leucin-rich glioma-inactivated protein 1 (LGI1). We also describe illustrative examples of situations in which genetics and immunology meet in the complex pathways that underlie seizures and epilepsy.

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Cellular localization of metabotropic glutamate receptors in cortical tubers and subependymal giant cell tumors of tuberous sclerosis complex

Cited by 53 publications

References 71 publications

Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice

Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

Seizures and Epilepsies due to Channelopathies and Neurotransmitter Receptor Dysfunction: A Parallel between Genetic and Immune Aspects

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