Immunohistochemical expression of fibroblast growth factor-2 in developing human cerebrum and epilepsy-associated malformations of cortical development

Abstract

To elucidate the biological significance of fibroblast growth factor-2 (FGF-2) expression in epilepsy-associated malformations of cortical development, immunohistochemical expression of FGF-2 was investigated in the developing human cerebral mantles obtained from 30 autopsy cases of fetuses, stillborn infants and children ranging from 12 weeks gestation to 15 years old, and 70 surgically-resected corticectomy specimens from patients with medically intractable epilepsy, including: group I, 12 tubers of tuberous sclerosis; group II, 24 cases of focal cortical dysplasia (FCD) with balloon cells (BC); group III, 11 FCD without BC; group IV, 23 histologically normal-appearing neocortices from patients with Rasmussen encephalitis, cystic-gliotic encephalopathy, temporal lobe epilepsy; and group V, 14 normal-appearing neocortices adjacent to dysplastic lesions from groups I and II. FGF-2 expression was detected in a population of matrix cells and/or neuroblasts within the ventricular zone in fetuses younger than 19 weeks gestation. Nuclei of glioblasts and immature astrocytes were also positive for FGF-2 in cases older than 18 weeks gestation. FGF-2 expression was not detected in immature cortical plate neurons. Astrocytes and ependymal cells were positive for FGF-2 in the postnatal brains. Choroid plexus epithelium was strongly positive for FGF-2 in all cases examined. Among the corticectomy specimens, the cytoplasms and/or nuclei of dysmorphic neurons (DNs) and BCs in groups I and II were variably positive for FGF-2. The proportions of FGF-2 immunoreactive cells (FGF-2-IR%) was significantly higher in groups I (36.9 ± 9.6) and II (45.1 ± 7.0) than in groups III (21.0 ± 5.7), IV (14.4 ± 4.7) and V (24.3 ± 10.3), and that in group V was higher than in group IV (P<0.01). These results indicate that FGF-2 upregulation in DNs and BCs is an important feature common to groups I and II, and suggest that BCs and DNs in these groups represent disturbed gliogenesis from matrix cells and disturbed maturation of cortical neurons from migrating neuroblasts, respectively.

Implication of fibroblast growth factors in epileptogenesis-associated circuit rearrangements

“…The data support the notion that FGF2 favors epilepsy development by altering gliogenesis and maturation of cortical neurons from migrating neuroblasts (Ueda et al, 2011). …”

“…Neurotrophic factors (NTFs) appear to be very strong candidates, because an extensive literature demonstrates their involvement in each of the above-mentioned cellular alterations associated with epileptogenesis (Simonato et al, 2006; Simonato and Zucchini, 2010): not only their trophic effects suggest an involvement in cell death, neurogenesis and axonal sprouting, but they also exert functional effects at the synaptic level, with distinct modulatory actions at excitatory and inhibitory synapses (Schinder and Poo, 2000). Furthermore, NTFs are greatly involved in brain development, and epileptogenesis is thought to recapitulate several aspects of developmental processes (Kim et al, 2010; Simonato and Zucchini, 2010; Ueda et al, 2011). …”

Morphogens in the Wiring of the Nervous System

“…In addition to rodent studies, the implication of FGF2 has been investigated in human epilepsy-associated malformations of cortical development by autoptic analysis and corticectomy specimens. The data support the notion that FGF2 favors epilepsy development by altering gliogenesis and maturation of cortical neurons from migrating neuroblasts (Ueda et al, 2011).…”

“…Neurotrophic factors (NTFs) appear to be very strong candidates, because an extensive literature demonstrates their involvement in each of the above-mentioned cellular alterations associated with epileptogenesis (Simonato et al, 2006;Simonato and Zucchini, 2010): not only their trophic effects suggest an involvement in cell death, neurogenesis and axonal sprouting, but they also exert functional effects at the synaptic level, with distinct modulatory actions at excitatory and inhibitory synapses (Schinder and Poo, 2000). Furthermore, NTFs are greatly involved in brain development, and epileptogenesis is thought to recapitulate several aspects of developmental processes (Kim et al, 2010;Simonato and Zucchini, 2010;Ueda et al, 2011).…”

Surgical pathology of epilepsy‐associated non‐neoplastic cerebral lesions: A brief introduction with special reference to hippocampal sclerosis and focal cortical dysplasia

“…56 These histological features are very similar to those seen in cortical tubers of tuberous sclerosis complex (TSC-tubers) (Figure 6), 48,57 despite different clinical presentations. Recent evidence has suggested factors significant in the morphogenesis of abnormal cells in dysplastic cortex of TSC-tubers and FCD type IIb, including aberrant expression of cytoskeletal proteins, 58,59 stem cell markers such as nestin, 60 CD34 class II, 61 neurotrophin receptors 62 , fibroblast growth factor-2 63,64 and cortical layer markers 65 as well as altered mTOR signaling pathways. 66,67 Some of these studies, at least from the neuropathological point of view, provided supportive evidence that BCs and dysmorphic neurons represent disturbed gliogenesis from matrix cells or radial glia and disturbed maturation of cortical neurons from migrating neuroblasts or intermediate progenitor cells, respectively.…”