gms | German Medical Science

Objective: Focal cortical dysplasia (FCD), a malformation of cerebrocortical development, is regarded as a major cause of pharmaco-resistant focal epilepsy thus frequently becoming object to neurosurgical treatment. Severe focal cortical dysplasia (FCD 2b) is characterized by distinct cortical dyslamination, dysmorphic neurons and balloon cells (BC). However, little is known about the cellular identity of BC, their intercellular interactions and possible impact on epileptogenicity. An approach to a structural and morphological characterization of BC and their potential cellular integration in a severely dysplastic, epileptogenic cortex is subject of the current study.

Method: Layer-specific protein expression (Reelin, Calbindin, SMI32, Parvalbumin, TLE4) and inhibitory interneuron status (GAD65/67) were studied by immunohistological techniques including double immunolabeling. N=29 specimens with neuropathologically confirmed FCD 2b were analyzed, in addition analysis of neuronal stem cell marker expression (Oct4, SOX2, c-myc, Vimentin, Nestin) in n=3 specimens was carried out; the findings were compared to a control group with (n=6) and without epilepsy (n=4 post mortem). Cortical neuronal fiber structure was visualized by Bielschowsky silver staining. Statistical analysis following quantification of layer-specific neuronal subpopulations and BC and morphological study of stem cell marker expression in BC was performed.

Results: Using lamina-specific markers we found that BC can be located all over the dysplastic cortex without a lamina of preference. Moreover, morphological study suggests that BC intercommunicate with cortical neurons and receive inhibitory input. Furthermore, BC show pluripotent stem cell marker expression: Whereas a colocalization of the analyzed stem cell marker expression was observed for Vimentin, Nestin, SOX2 and c-myc, there was a cellular subpopulation solely immunopositive for Oct4.

Conclusions: Our findings suggest that a migration disorder underlying the layer-unspecific cortical localization of BC is unlikely. Moreover, we observed signs of intercellular interaction of BC that still have to be analyzed in detail. In addition, there is evidence of an activation of the mTORC1 cascade resulting in an upregulation of pluripotent stem cell markers in BC. The marker expression pattern characterizes subpopulations of BC possibly indicating a differing level of differentiation or cellular identity.