Developmental lineage of cell types in cortical dysplasia with balloon cells

Abstract

Focal cortical dysplasia type IIB with Ballon cells is a developmental malformation of the cerebral cortex highly associated with epilepsy. As a strategy to define the embryonic origin and neurochemical phenotype of cells in this disease, we probed specimens (n = 10) resected during epilepsy surgery with a panel of 13 antibodies recognizing proteins associated with (i) specific progenitor cell types including brain lipid binding protein (BLBP), collapsin response mediator protein 4 (CRMP4), Dlx1, Dlx2, GFAPdelta, MASH1, Otx1, Pax6, vimentin and phosphorylated vimentin and (ii) excitatory or inhibitory neurochemical phenotypes such as the vesicular glutamate transporters-1 and 2 (VGLUT-1, VGLUT-2), or the vesicular GABA transporter (VGAT). Balloon cells and large dysplastic neurons in all specimens expressed Otx1, phospho-vimentin, Pax6 and BLBP, proteins normally expressed by cells in the embryonic ventricular zone. A subpopulation of balloon cells expressed MASH-1 also expressed in the ventricular zone. Most balloon cells and dysplastic neurons were VGLUT2 immunoreactive, whereas none expressed Dlx1 or Dlx2, markers for inhibitory cells derived from the medial ganglionic eminence and few expressed VGAT, found in GABAergic interneurons. Otx1 mRNA expression and Dlx1 mRNA absence was confirmed by single cell RT-PCR. A subpopulation of balloon cells was labelled with CRMP4 and GFAPdelta, markers specific for newly generated cells derived from the adult subventricular zone. Detection of Otx1, phospho-vimentin, Pax6 and BLBP expression but absence of Dlx1/Dlx2 expression suggests that balloon cells and dysplastic neurons derive from radial glial cells in the telencephalic ventricular zone and not the medial ganglionic eminence. VGLUT expression argues that dysplastic neurons may be glutamatergic. CRMP-4 and GFAPdelta expression suggests that new cells may arrive in focal cortical dysplasia, perhaps deriving in part from the subventricular zone. These findings provide a developmental lineage model in which balloon cells and dysplastic neurons are derived from radial glial progenitor cells.

mTOR Signaling in Epilepsy: Insights from Malformations of Cortical Development

“…Loss of Tsc1 or Pten in hippocampal neurons in vitro lead to an increase in the ratio of excitation to inhibition at the network level, although through divergent mechanisms (Weston et al 2014). These findings provide experimental support to observations in human tuber and FCDIIB specimens, which show reduced numbers of GABAergic inhibitory interneurons (White et al 2001;Calcagnotto et al 2005;Lamparello et al 2007).…”

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

“…In our previous studies, we showed that GFAPd is expressed in balloon cells in focal cortical dysplasia and hemimegalencephaly, and in giant cells in tuberous sclerosis complex (Lamparello et al, 2007;Martinian et al, 2009). 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.…”

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Evaluation of doublecortin expression patterns in FCD I, compared with normal developing and mature cortex, indicates delayed or abnormal cortical maturation rather than ongoing cytogenesis [138]. Moreover, the application of different cortical layer markers in the evaluation of FCD I and FCD II [109,139] demonstrates that FCD I cases in younger patients were characterized by abnormal expression in layer II for Tbr1 and Otx1, whereas FCDII showed distinct labeling of balloon cells (Pax6, ER81, and Otx1) and dysmorphic neurones (Tbr 1, N200, and Map1b), supporting origins from radial glia (as previously shown [139]) and intermediate progenitor cells, respectively [109].…”