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.

Tuberous sclerosis complex (TSC) is a multisystem disorder that affects numerous organ systems. Brain lesions that form during development, known as tubers, are highly associated with epilepsy, cognitive disability, and autism. Following the identification of two genes and their encoded proteins, TSC1 (hamartin) and TSC2 (tuberin), responsible for TSC, identification of several downstream protein cascades that might be affected in TSC have been discovered. Of primary importance is the mammalian target of rapamycin pathway that controls cell growth and protein synthesis. The mechanisms governing brain lesion growth have not been fully identified but likely altered regulation of the mammalian target of rapamycin cascade by hamartin and tuberin during development leads to aberrant cell growth. Secondary effects of TSC gene mutations might disrupt normal neuronal migration and cerebral cortical lamination. Numerous studies have identified changes in gene and protein expression in animal models of TSC and in human TSC brain specimens that contribute to altered brain cytoarchitecture. This review will provide an overview of the neurobiological aspects of TSC.

No abstract

No abstract