Cytoarchitectural alterations are widespread in cerebral cortex in tuberous sclerosis complex |
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Authors: | Leah?Marcotte Eleonora?Aronica Marianna?Baybis Email author" target="_blank">Peter?B?CrinoEmail author |
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Institution: | Department of Neurology, PENN Epilepsy Center, University of Pennsylvania Medical Center, Philadelphia, 19104, USA. |
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Abstract: | Tubers are cerebral cortical developmental malformations associated with epilepsy and autism in tuberous sclerosis complex
(TSC). The disparity between tuber number and severity of neurological impairment often observed in TSC led us to hypothesize
that microscopic structural abnormalities distinct from tubers may occur in TSC. Serial frontal to occipital lobe sections
were prepared from five postmortem TSC brain specimens. Sections were probed with cresyl violet stain or NeuN antibodies to
define cytoarchitectural abnormalities and phospho-S6 (Ser235/236) antibodies to define mammalian target of rapamycin complex
1 (mTORC1) pathway activation. Tubers identified in all specimens (mean, 5 tubers per brain specimen) were defined by abnormal
cortical lamination, dysmorphic neurons, and giant cells (GCs) and exhibited robust phospho-S6 immunolabeling. Histopathological
analysis of non-tuber cortices demonstrated that 32% of the sections exhibited microscopic cytoarchitectural alterations,
whereas 68% of the sections did not. Four types of morphological abnormalities were defined including: (1) focal dyslamination,
(2) heterotopic neurons, (3) small collections of giant cells (GCs) and neurons we termed “microtubers”, (4) isolated GCs
we termed “sentinel” cells. When compared with control cortex, phospho-S6 labeling was enhanced in microtubers and sentinel
cells and in some but not all areas of dyslamination. There are microscopic cytoarchitectural abnormalities identified in
postmortem TSC brain specimens that are distinct from tubers. mTORC1 cascade activation in these areas supports a widespread
effect of TSC1 or TSC2 mutations on brain development. Tubers may represent the most dramatic developmental abnormality in TSC; however, more regionally
pervasive yet subtle abnormalities may contribute to neurological disability in TSC. |
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