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Cytoarchitectural alterations are widespread in cerebral cortex in tuberous sclerosis complex

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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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Acknowledgments

This work was supported by NS045877, NS045021, and Department of Defense CDMRP-TSC Program (PBC); the National Epilepsy Fund-“Power of the Small,” Hersenstichting Nederland (NEF 02-10 and NEF 05-11) and Stichting Michelle (M06.011; EA). We humbly thank TSC patients and families who sponsored brain donation for research and the Brain and Tissue Bank of the University of Maryland.

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Authors and Affiliations

  1. Department of Neurology, PENN Epilepsy Center, University of Pennsylvania Medical Center, 3 West Gates Bldg., 3400 Spruce St., Philadelphia, PA, 19104, USA

    Leah Marcotte, Marianna Baybis & Peter B. Crino

  2. Netherlands Institute for Neuroscience, Amsterdam, The Netherlands

    Eleonora Aronica

  3. Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Eleonora Aronica

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  1. Leah Marcotte
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  2. Eleonora Aronica
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  3. Marianna Baybis
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  4. Peter B. Crino
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Correspondence to Peter B. Crino.

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Marcotte, L., Aronica, E., Baybis, M. et al. Cytoarchitectural alterations are widespread in cerebral cortex in tuberous sclerosis complex. Acta Neuropathol 123, 685–693 (2012). https://doi.org/10.1007/s00401-012-0950-3

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  • DOI: https://doi.org/10.1007/s00401-012-0950-3

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