Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis

Koene, Linda M. C.; Niggl, Eva; Wallaard, Ilse; Onori, Martina Proietti; Rotaru, Diana C.; Elgersma, Ype

doi:10.1172/jci.insight.150120

Cited by 12 publications

(7 citation statements)

References 79 publications

(112 reference statements)

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“…Thus, these cell autonomous reductions in GABAergic transmission onto postsynaptic excitatory neurons may not be sufficient to drive circuit hyperexcitability when they co-occur with either diminished excitatory input or reduced intrinsic excitability in PYR neurons. In line with this conclusion, Tsc1 mutations that promote increases in PYR intrinsic excitability co-occurs with hyperexcitability (Abs et al, 2013;Koene et al, 2021).…”

Section: Dual Roles For Reduced Inhibition In Seizure Susceptibility ...supporting

confidence: 57%

Paradoxical Hyperexcitability in Disorders of Neurodevelopment

Antoine

2022

Front. Mol. Neurosci.

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Autism Spectrum Disorder (ASD), Rett syndrome (RTT) and Angelman Syndrome (AS) are neurodevelopmental disorders (NDDs) that share several clinical characteristics, including displays of repetitive movements, developmental delays, language deficits, intellectual disability, and increased susceptibility to epilepsy. While several reviews address the biological basis of non-seizure-related ASD phenotypes, here, I highlight some shared biological mechanisms that may contribute to increased seizure susceptibility. I focus on genetic studies identifying the anatomical origin of the seizure phenotype in loss-of-function, monogenic, mouse models of these NDDs, combined with insights gained from complementary studies quantifying levels of synaptic excitation and inhibition. Epilepsy is characterized by a sudden, abnormal increase in synchronous activity within neuronal networks, that is posited to arise from excess excitation, largely driven by reduced synaptic inhibition. Primarily for this reason, elevated network excitability is proposed to underlie the causal basis for the ASD, RTT, and AS phenotypes. Although, mouse models of these disorders replicate aspects of the human condition, i.e., hyperexcitability discharges or seizures on cortical electroencephalograms, measures at the synaptic level often reveal deficits in excitatory synaptic transmission, rather than too much excitation. Resolving this apparent paradox has direct implications regarding expected outcomes of manipulating GABAergic tone. In particular, in NDDs associated with seizures, cortical circuits can display reduced, rather than normal or increased levels of synaptic excitation, and therefore suggested treatments aimed at increasing inhibition could further promote hypoactivity instead of normality. In this review, I highlight shared mechanisms across animal models for ASD, RTT, and AS with reduced synaptic excitation that nevertheless promote hyperexcitability in cortical circuits.

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Section: Dual Roles For Reduced Inhibition In Seizure Susceptibility ...supporting

confidence: 57%

Paradoxical Hyperexcitability in Disorders of Neurodevelopment

Antoine

2022

Front. Mol. Neurosci.

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“…The First is an anti-inflammatory effect: mTOR inhibitors directly inhibited microglial accumulation in the lipopolysaccharide-induced neuroinflammation model ( Yang et al, 2017 ), a focal ischemic stroke model ( Guden et al, 2021 ), and a kainic acid-induced seizure model ( Huang et al, 2021 ). The second is the effect on epileptogenicity: in the TSC1-knockout mouse model, an mTOR-inhibitor rescued the excitation/inhibition imbalance by changing the multiple ion channels in the hippocampus ( Koene et al, 2021 ). Abs et al ( Abs et al, 2013 ) reported that mTOR overactivation by acute biallelic deletion of TSC1 in healthy adult mice facilitated the development of seizures without obvious cortical tubers within a few days and that rapamycin treatment completely stopped the seizures.…”

Section: Discussionmentioning

confidence: 99%

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

Kagitani‐Shimono

Kato

Soeda

et al. 2023

NeuroImage: Clinical

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“… 26 , 34 – 36 Beyond that, rapamycin could be useful for seizure control in TSC in both animal and human studies. 37 – 40 Several ASMs are the substrate and inducer of CYP3A4 and phosphoglycolate phosphatase, which may influence the metabolism of mTOR inhibitor, 41 , 42 but this effect was not observed with VGB. 43 Vogel et al 44 showed that increased expression of transcripts in the mTOR pathway and autophagy was suppressed in the human retinal pigment epithelial cells ARPE19 cultured in VGB, and this effect could be attenuated by the mTOR inhibitor (Torin 2).…”

Section: Discussionmentioning

confidence: 99%

Vigabatrin-associated brain abnormalities on MRI in tuberous sclerosis complex patients with infantile spasms: are they preventable?

Wan

Wang

et al. 2022

Ther Adv Neurol Disord

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Background: Vigabatrin (VGB) is currently the most widely prescribed first-line medication for individuals with infantile spasms (IS) and especially for those with tuberous sclerosis complex (TSC), with demonstrated efficacy. Meanwhile, its adverse events, such as vigabatrin-associated brain abnormalities on magnetic resonance imaging (MRI; VABAM), have also been widely reported. Objectives: The objectives of this study were to observe the occurrences of VABAM in patients with IS caused by TSC (IST) and further explore the associated risk factors. Methods: Children with IS receiving VGB were recruited from our institution; clinical, imaging, and medication data were collected. Cerebral MRI was reviewed to determine the occurrence of VABAM. Group comparisons (IS caused by TSC and other etiologies) were performed; subgroup analyses on IST were also performed. Next, a retrospective cohort study of children taking VGB was conducted to explore risk/protective factors associated with VABAM. Results: The study enrolled 172 children with IS who received VGB. VABAM was observed in 38 patients (22.1%) with a peak dosage of 103.5 ± 26.7 mg/kg/day. Subsequent analysis found the incidence of VABAM was significantly lower in the 80 patients with IST than in the 92 patients with IS caused by other etiologies (10% versus 32.6%, p-value < 0.001). In subgroup analyses within the IST cohort, VABAM was significantly lower in children who received concomitant rapamycin therapy. Univariate and multivariate logistic regression analysis of the 172 IS children showed that treatment with rapamycin was the independent factor associated with a lower risk of VABAM; similar results were observed in the survival analysis. Conclusion: The incidence of VABAM was significantly lower in IST patients. Further research is needed to examine the mechanisms that underlie this phenomenon and to determine if treatment with rapamycin may reduce the risk of VABAM.

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Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis

Cited by 12 publications

References 79 publications

Paradoxical Hyperexcitability in Disorders of Neurodevelopment

Paradoxical Hyperexcitability in Disorders of Neurodevelopment

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

Vigabatrin-associated brain abnormalities on MRI in tuberous sclerosis complex patients with infantile spasms: are they preventable?

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