Cytomegalic Interneurons

André, Véronique; Wu, Nanping; Yamazaki, Irene; Nguyen, Snow; Fisher, Robin S.; Vinters, Harry V.; Mathern, Gary W.; Levine, Michael S.; Cepeda, Carlos

doi:10.1097/01.jnen.0000240473.50661.d8

Cited by 68 publications

(16 citation statements)

References 53 publications

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“…The following description of morphological cellular abnormalities is largely based on our own studies using biocytin and immunocytochemical staining in tissue samples from children (ages 2 months to 14 years) with CD [10,67–69]. CD type I contains misoriented pyramidal neurons, pyramidal neurons with tortuous processes, and hypertrophic pyramidal neurons with otherwise normal morphology.…”

Section: Architectural and Cellular Abnormalities In CDmentioning

confidence: 99%

“…Unusually dense Nissl substance with wild appearance and abnormal distribution of neurofilament proteins can be observed [9,70,71]. Cytomegalic interneurons are another abnormal cell type found in CD type II (in particular associated with hemimegalencephaly, HME) [67]. They are characterized by their large size, 2–3 times larger than normal interneurons.…”

Section: Architectural and Cellular Abnormalities In CDmentioning

confidence: 99%

“…Cytomegalic interneurons are similar to basket cells and also have increased number of dendrites. They label for calbindin and parvalbumin but not for calretinin, suggesting they may originate in the medial ganglionic eminence [67]. Balloon cells are the hallmark of CD type IIb.…”

Section: Architectural and Cellular Abnormalities In CDmentioning

confidence: 99%

“…However, the sensitivity of these cells to GABA is not changed in CD tissue compared to nondysplastic tissue [84]. Similar to cytomegalic pyramidal neurons, cytomegalic GABAergic interneurons are hyperexcitable and display spontaneous membrane depolarizations and bursting activity [67]. …”

Section: In Vitro Electrophysiology Of CD Tissuementioning

confidence: 99%

“…Of the different dysplastic cells, cytomegalic pyramidal neurons are more likely to be epileptogenic, while balloon cells are not epileptogenic [85]. On the other hand, the cytomegalic interneurons have been shown to be hyperexcitable and display spontaneous membrane depolarizations similar to paroxysmal depolarizing shifts, making them potential generators of epileptic activity [67]. …”

Section: Proposed Mechanisms Of Epileptogenesis In CDmentioning

confidence: 99%

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Basic Mechanisms of Epileptogenesis in Pediatric Cortical Dysplasia

et al. 2014

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SUMMARY Cortical dysplasia (CD) is a neurodevelopmental disorder due to aberrant cell proliferation and differentiation. Advances in neuroimaging have proven effective in early identification of the more severe lesions and timely surgical removal to treat epilepsy. However, the exact mechanisms of epileptogenesis are not well understood. This review examines possible mechanisms based on anatomical and electrophysiological studies. CD can be classified as CD type I consisting of architectural abnormalities, CD type II with the presence of dysmorphic cytomegalic neurons and balloon cells, and CD type III which occurs in association with other pathologies. Use of freshly resected brain tissue has allowed a better understanding of basic mechanisms of epileptogenesis and has delineated the role of abnormal cells and synaptic activity. In CD type II, it was demonstrated that balloon cells do not initiate epileptic activity, whereas dysmorphic cytomegalic and immature neurons play an important role in generation and propagation of epileptic discharges. An unexpected finding in pediatric CD was that GABA synaptic activity is not reduced, and in fact, it may facilitate the occurrence of epileptic activity. This could be because neuronal circuits display morphological and functional signs of dysmaturity. In consequence, drugs that increase GABA function may prove ineffective in pediatric CD. In contrast, drugs that counteract depolarizing actions of GABA or drugs that inhibit the mammalian target of rapamycin (mTOR) pathway could be more effective.

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Section: Architectural and Cellular Abnormalities In CDmentioning

confidence: 99%

Section: Architectural and Cellular Abnormalities In CDmentioning

confidence: 99%

Section: Architectural and Cellular Abnormalities In CDmentioning

confidence: 99%

Section: In Vitro Electrophysiology Of CD Tissuementioning

confidence: 99%

Section: Proposed Mechanisms Of Epileptogenesis In CDmentioning

confidence: 99%

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Basic Mechanisms of Epileptogenesis in Pediatric Cortical Dysplasia

et al. 2014

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Cell‐specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers

Talos

Kwiatkowski

Cordero

et al. 2008

Annals of Neurology

140

136

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Objective-Genetic loss of TSC1/TSC2 function in tuberous sclerosis complex (TSC) results in overactivation of the mammalian target of rapamycin complex 1 pathway, leading to cellular dysplasia. We hypothesized that the dysplastic cells in TSC tubers are heterogeneous, including separable classes on a neuronal-glial spectrum, and that these dysplastic cells express glutamate receptor (GluR) patterns consistent with increased cortical network excitability.Methods-Surgically resected human cortical tubers and nondysplastic epileptic cortical samples were analyzed by double-label immunocytochemistry for coexpression of neuronal and glial markers, the TSC1/TSC2 pathway downstream molecule phospho-S6 (pS6) and GluR subunits, and compared with control cortical tissue. Western blotting was used to quantify changes in GluR subunit expression in tubers versus controls.Results-We demonstrate that cortical tubers contain a broad spectrum of cell types including disoriented pyramidal cells, dysplastic neurons, giant neuroglial cells, dysplastic astroglia, and reactive astrocytes. Dysplastic neurons, giant cells, and dysplastic astroglia express high levels of pS6 and demonstrate altered GluR subunit composition, resembling those of normal immature neurons and glia. In contrast, nondysplastic neurons in TSC and non-TSC epileptic lesions express lower pS6 levels and display changes in GluR subunit expression that are distinct from the patterns seen in tuber dysplastic cells.Interpretation-This work significantly expands the spectrum of abnormal cells recognized in tubers beyond the classic tuber giant cell and demonstrates cell-specific abnormalities in GluR expression that may contribute to seizure pathogenesis in TSC. Furthermore, these results suggest that subunit-specific antagonists may be of potential use in the treatment of epilepsy in TSC.Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations in either the TSC1 or TSC2 gene. 1,2 TSC brain lesions are malformations of cortical development that include cortical tubers, white matter abnormalities, subependymal nodules, Although previous reports have recognized the occurrence of various dysplastic cell types within tubers beyond the classical giant cell, 4,20,21 we set out to classify the cellular pathology of these lesions in detail, using combined morphological and immunocytochemical criteria, including the use of neuronal and glial markers and phospho-S6 (pS6) to assess the mammalian target of rapamycin (mTOR) pathway dysfunction. In addition, given that TSC is a malformation of development, we explored the hypothesis that the abnormal cell types present in tubers express immature iGluRs patterns known to promote cortical network hyperexcitability, thereby possibly contributing to the epileptogenicity of these lesions. White and coworkers 22 previously reported that dysplastic neurons and giant cells express abnormal patterns of glutamate and GABA receptor subunit messenger RNA. To further determine whether neurotrans...

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