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Cytoarchitectural alterations are widespread in cerebral cortex in tuberous sclerosis complex
Leah Marcotte1, Eleonora Aronica, Marianna Baybis
1Department of Neurology, PENN Epilepsy Center, University of Pennsylvania Medical Center, Philadelphia, 19104, USA.
Acta Neuropathologica
|February 14, 2012
Summary
Microscopic brain abnormalities, distinct from tubers, were found in Tuberous Sclerosis Complex (TSC) postmortem samples. These subtle changes, including "microtubers" and "sentinel" cells, show mTORC1 activation, suggesting widespread developmental effects in TSC.
Area of Science:
- Neuroscience
- Developmental Biology
- Pathology
Background:
- Tuberous Sclerosis Complex (TSC) is characterized by tubers, which are cortical malformations linked to epilepsy and autism.
- A discrepancy often exists between the number of tubers and the severity of neurological deficits in TSC patients.
- This suggests that other, less apparent brain abnormalities may also contribute to neurological impairment in TSC.
Purpose of the Study:
- To investigate the presence of microscopic structural abnormalities in the brain beyond visible tubers in postmortem TSC specimens.
- To determine if these microscopic abnormalities are associated with the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway.
Main Methods:
- Postmortem brain sections from five TSC patients were analyzed.
- Histological staining (cresyl violet, NeuN) was used to identify cytoarchitectural abnormalities.
- Immunohistochemistry for phospho-S6 (Ser235/236) was performed to assess mTORC1 pathway activation.
Main Results:
- Tubers were identified in all specimens, showing abnormal lamination, dysmorphic neurons, giant cells (GCs), and strong phospho-S6 labeling.
- Microscopic cytoarchitectural alterations were found in 32% of non-tuber cortical sections.
- Four distinct microscopic abnormalities were defined: focal dyslamination, heterotopic neurons, "microtubers" (collections of GCs and neurons), and "sentinel" cells (isolated GCs).
- Enhanced phospho-S6 labeling was observed in microtubers and sentinel cells, and in some dyslaminated areas, indicating mTORC1 activation.
Conclusions:
- Microscopic cytoarchitectural abnormalities, separate from tubers, exist in TSC brains.
- The presence of mTORC1 activation in these subtle lesions suggests a broader impact of TSC1/TSC2 mutations on brain development.
- These pervasive microscopic abnormalities, in addition to tubers, may significantly contribute to the neurological disabilities seen in Tuberous Sclerosis Complex.
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