Internexin, MAP1B, and nestin in cortical dysplasia as markers of developmental maturity

Abstract

Cortical dysplasias (CD) are characterized histologically by disorganized cortical lamination and abnormally shaped neurons. We hypothesized that neurons within CD have failed to differentiate fully and may express proteins such as cytoskeletal elements characteristic of immature cells. Disrupted expression of certain cytoskeletal proteins, which have been implicated in neuronal polarity, process outgrowth, and migration, could result in disorganized cortical lamination. Thus, we probed two CD subtypes, focal CD (FCD) and hemimegalencephaly (HME), with antibodies specific for cytoskeletal proteins that are developmentally regulated in neural progenitor cells and neurons to define more fully the developmental phenotype of neurons within CD. Microtubule-associated protein 1B (MAP1B) and the intermediate filament (IF) protein nestin are enriched in neural progenitors, whereas MAP2B, phosphorylated and non-phosphorylated forms of medium (NFM) and high (NFH) molecular weight neurofilament (NF) proteins, as well as the light NF subunit (NFL) and IF protein alpha internexin are expressed in developing and mature neurons. Immunolabeling for internexin and MAP1B was more abundant in the most abnormally shaped neurons that populated dysplastic regions than in adjacent regions exhibiting milder cytoarchitectural abnormalities or control cortex. Nestin immunoreactivity was noted in large dysplastic and heterotopic neurons within the deeper cortical layers of CD specimens but not in normal cortex. In contrast, neurons in CD specimens also expressed cytoskeletal markers characteristic of differentiated neurons such as NF subunits and MAP2B. These findings suggest that the cytoarchitectural abnormalities in CD may reflect pathophysiological changes in the developing brain that disrupt expression of several key components of the neuronal cytoskeleton and may contribute to impaired migration of cortical neurons.

GFAPδ in radial glia and subventricular zone progenitors in the developing human cortex

“…Because at that time, GFAPd was only described in SVZ astrocytes (Roelofs et al, 2005), an area in which neural progenitors are located, we put forward the idea that the GFAPd subpopulation of balloon cells retains a progenitor phenotype or represents an influx of newly generated astrocytes from the SVZ. Several studies provided evidence that balloon cells in focal cortical dysplasia retain an embryonic phenotype and are derived from radial glial cells (Crino et al, 1997;Mizuguchi et al, 2002;Sisodiya et al, 2002;Thom et al, 2005). The fact that we found GFAPd expression in radial glia during brain development supports this view.…”

Activation of mammalian target of rapamycin in cytomegalic neurons of human cortical dysplasia

“…These findings are consistent with previous reports that mRNA for all neuronal filaments is increased in dysplastic neurons in FCD. 33,34 Our microarray study also demonstrated a dysregulation of other neurofilament genes in cytomegalic neurons of FCD (M. Sheldon and colleagues, unpublished data). These results, however, require further analysis that is beyond the scope of this study.…”

“…Both these tissues appeared normal. Dysplastic neurons are known to contain large amounts of several intermediate filaments, [33][34][35] although these proteins are not unique to abnormal neurons. In contrast, this NF-H antibody labeled almost exclusively cytomegalic neurons in our specimens.…”

Epilepsy and cortical dysplasias

“…Mixed seizure types may develop in the same patient. FCD regions are highly epileptogenic as determined by intraoperative electrocorticography [3,18]. Seizures in those patients with CD are particularly difficult to control with conventional antiepileptic drugs (AEDs) and many individuals will require surgical intervention.…”