Development of cortical malformations in BCNU-treated rat, model of cortical dysplasia.
Cortical dysplasia (CD) comprises a wide range of cerebral cortex alterations ranging from severe brain malformations to local disruption of the cortical structure. Most hypotheses focused on the role of embryonic/perinatal development insults as the main cause for the majority of CD. Rats with prenatal exposure to BCNU (1-3-bis-chloroethyl-nitrosurea) represent an injury-based model and reproduce many anatomical features seen in human patients with CD, such as altered cortical layering and the presence of heterotopia and dysmorphic/heterotopic neurons. With the aim to investigate the formation and evolution of CD during development, we analysed the expression of a panel of layer-specific genes (Nurr1, Er81, Ror-β and Cux2, markers of layers VI, V, IV and superficial layers, respectively) in BCNU-treated cortices from E17 to postnatal day 14. By means of appropriate immunohistochemical markers, we also analysed the structural organization of embryonic ventricular zone and of glial and axonal fibres, substrates supporting radial and tangential migration, respectively. The main results of the present study are: (i) the ventricular zone appeared disorganized and the neuroependyma was partially disrupted; (ii) radial glia scaffold and tangential fibres were deeply disarranged, thus explaining the neuronal migration defects; (iii) cortical heterotopia were detectable by E19, whereas periventricular heterotopia were detectable after birth; (iv) both cortical and periventricular heterotopia showed a pseudo-laminar structure, with cells of the upper cortical layers in the core of the nodules and cells of layer IV and V at their border; (v) the distribution of GABAergic cells was altered since the embryonic stages, as a consequence of the derangement of tangential fibres. Our analysis sheds light on how a malformed cortex develops after a temporally discrete environmental insult and adds additional knowledge on specific aspects of the etiopathogenesis of CD.
Fondazione I.R.C.C.S. Istituto Neurologico C. Besta, Via Celoria 11,20133 Milan, Italy.
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Moroni
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Cipelletti
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Regondi
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D000818:Animals; D000831:Animals, Newborn; D002330:Carmustine / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology / Q000235:genetics / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006801:Humans; D054220:Malformations of Cortical Development / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D009421:Nervous System Malformations / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens; D002330:Carmustine