Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement

Hsieh, Lawrence S.; Wen, John H.; Claycomb, Kumiko I.; Huang, Yingqun; Harrsch, Felicia A.; Naegele, Janice R.; Hyder, Fahmeed; Buchanan, Gordon F.; Bordey, Angélique

doi:10.1038/ncomms11753

Cited by 91 publications

(149 citation statements)

References 56 publications

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“…These data do not contradict the previous findings showing that epilepsy triggers angiogenesis. 28 Finally, an important finding is that the blood vessel alterations in mice with a focal or a global MCD were quite similar, but only hypervascularization in the focal MCD was partially rescued by 0.5 mg/kg rapamycin treatment. Another question relates to the outcome of altered vascularization on seizure activity.…”

Section: Discussionmentioning

confidence: 91%

“…28,34 In this model, a focal MCD in the somatosensory cortex did not lead to seizures while a focal MCD in the medial prefrontal cortex led to seizures that were visible starting at P21. In addition, using the transgenic Tsc1 mice with global cortical malformation leads to seizure activity, preventing us from assessing whether the presence of dysmorphic neurons alone without seizure is sufficient to induce hypervascularization.…”

Section: Mice With Focal MCD Display Hypervascularizationmentioning

confidence: 88%

“…We introduced a concentration of Rheb CA that does not lead to seizures following IUE in the medial prefrontal cortex. 28 There was no increase in GFAP immunostaining ( Figure S1). In both conditions, a red fluorescent protein (-tdTomato-)-expressing reporter was coelectroporated to visualize the targeted cells.…”

Section: Mice With Focal MCD Display Hypervascularizationmentioning

confidence: 96%

“…28 However, such a rapamycin dose severely altered mouse growth. 28 However, such a rapamycin dose severely altered mouse growth.…”

Section: Decreasing Mtor Activity With a Nonsaturating Dose Of Rapamentioning

confidence: 99%

“…18,19 Such vascular alteration is conceivable considering that mTOR hyperactivity in TSC and FCDII-related MCD in mice and humans leads to increased production of vascular endothelial growth factor (VEGF) that regulates angiogenesis. The models consisted of wild-type mice containing a mTOR-dependent focal malformation in the somatosensory cortex that does not lead to seizures 28 and transgenic mice containing conditional Tsc1 null pyramidal neurons and astrocytes in the forebrain generating a global malformation associated with seizures. Another unaddressed question is whether the vasculature alterations are rapamycin-sensitive and thus mTOR-dependent.…”

Section: Introductionmentioning

confidence: 99%

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Hypervascularization in mTOR‐dependent focal and global cortical malformations displays differential rapamycin sensitivity

et al. 2019

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Objectives Patients with mammalian target of rapamycin (mTOR)–dependent malformations of cortical development (MCDs) associated with seizures display hyperperfusion and increased vessel density of the dysmorphic cortical tissue. Some studies have suggested that the vascular defect occurred independently of seizures. Here, we further examined whether hypervascularization occurs in animal models of global and focal MCD with and without seizures, and whether it is sensitive to the mTOR blocker, rapamycin, that is approved for epilepsy treatment in tuberous sclerosis complex. Methods We used two experimental models of mTOR‐dependent MCD consisting of conditional transgenic mice containing Tsc1null cells in the forebrain generating a global malformation associated with seizures and of wild‐type mice containing a focal malformation in the somatosensory cortex generated by in utero electroporation (IUE) that does not lead to seizures. Alterations in blood vessels and the effects of a 2‐week–long rapamycin treatment on these phenotypes were assessed in juvenile mice. Results Blood vessels in both the focal and global MCDs of postnatal day 14 mice displayed significant increase in vessel density, branching index, total vessel length, and decreased tissue lacunarity. In addition, rapamycin treatment (0.5 mg/kg, every 2 days) partially rescued vessel abnormalities in the focal MCD model, but it did not ameliorate the vessel abnormalities in the global MCD model that required higher rapamycin dosage for a partial rescue. Significance Here, we identified hypervascularization in mTOR‐dependent MCD in the absence of seizures in young mice, suggesting that increased angiogenesis occurs during development in parallel to alterations in corticogenesis. In addition, a predictive functional outcome is that dysplastic neurons forming MCD will have better access to oxygen and metabolic supplies via their closer proximity to blood vessels. Finally, the difference in rapamycin sensitivity between a focal and global MCD suggest that rapamycin treatment will need to be titrated to match the type of MCD.

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Section: Discussionmentioning

confidence: 91%

Section: Mice With Focal MCD Display Hypervascularizationmentioning

confidence: 88%

Section: Mice With Focal MCD Display Hypervascularizationmentioning

confidence: 96%

“…28 However, such a rapamycin dose severely altered mouse growth. 28 However, such a rapamycin dose severely altered mouse growth.…”

Section: Decreasing Mtor Activity With a Nonsaturating Dose Of Rapamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hypervascularization in mTOR‐dependent focal and global cortical malformations displays differential rapamycin sensitivity

et al. 2019

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Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia

Koh

Jang

et al. 2021

Annals of Neurology

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Objective: Low-level somatic mosaicism in the brain has been shown to be a major genetic cause of intractable focal epilepsy. However, how a relatively few mutation-carrying neurons are able to induce epileptogenesis at the local network level remains poorly understood. Methods: To probe the origin of epileptogenesis, we measured the excitability of neurons with MTOR mutation and nearby nonmutated neurons recorded by whole-cell patch-clamp and array-based electrodes comparing the topographic distribution of mutation. Computational simulation is used to understand neural network-level changes based on electrophysiological properties. To examine the underlying mechanism, we measured inhibitory and excitatory synaptic inputs in mutated neurons and nearby neurons by electrophysiological and histological methods using the mouse model and postoperative human brain tissue for cortical dysplasia. To explain non-cell-autonomous hyperexcitability, an inhibitor of adenosine kinase was injected into mice to enhance adenosine signaling and to mitigate hyperactivity of nearby nonmutated neurons. Results: We generated mice with a low-level somatic mutation in MTOR presenting spontaneous seizures. The seizuretriggering hyperexcitability originated from nonmutated neurons near mutation-carrying neurons, which proved to be less excitable than nonmutated neurons. Interestingly, the net balance between excitatory and inhibitory synaptic inputs onto mutated neurons remained unchanged. Additionally, we found that inhibition of adenosine kinase, which affects adenosine metabolism and neuronal excitability, reduced the hyperexcitability of nonmutated neurons. Interpretation: This study shows that neurons carrying somatic mutations in MTOR lead to focal epileptogenesis via non-cell-autonomous hyperexcitability of nearby nonmutated neurons.

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Phenotypic and genotypic characterization of NPRL3‐related epilepsy: Two case reports and literature review

Yang,

Wang,

Qin

et al. 2023

Epilepsia Open

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Nitrogen permease regulator‐like 3 (NPRL3) has been reported to play a role in seizure onset. The principal manifestation of NPRL3‐related epilepsy is a range of epilepsy‐associated syndromes, such as familial focal epilepsy with variable foci (FFEVF), sleep‐related hypermotor epilepsy (SHE), and temporal lobe epilepsy (TLE). The association between phenotype and genotype of NPRL3 mutations remains inadequately described. This study aimed to explore the phenotypic and genotypic spectra of NPRL3‐related epilepsy. We reported two novel NPRL3 variants in two unrelated epilepsy cases, including a nonsense (c.1174C>T, p.Gln392*) and a missense variant (c.1322C>T, p.Thr441Met). Following a review of the literature, a total of 116 cases of NPRL3‐related epilepsy were assessed, mostly with nonsense and frameshift mutations. Our findings suggest that patients harboring various NPRL3 variants exhibit variable clinical manifestations. In addition, it may be worthwhile to consider the existence of NPRL3 mutations in epilepsy patients with a family history. This study provides useful information for the treatment and prognosis by expanding the phenotypic and genotypic spectrum of NPRL3‐related epilepsy.

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Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement

Cited by 91 publications

References 56 publications

Hypervascularization in mTOR‐dependent focal and global cortical malformations displays differential rapamycin sensitivity

Hypervascularization in mTOR‐dependent focal and global cortical malformations displays differential rapamycin sensitivity

Non–Cell Autonomous Epileptogenesis in Focal Cortical Dysplasia

Phenotypic and genotypic characterization of NPRL3‐related epilepsy: Two case reports and literature review

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