Genesis of heterotopia in BCNU model of cortical dysplasia, detected by means of in utero electroporation.
Derangements of cortical development can cause a wide spectrum of malformations, generally termed 'cortical dysplasia' (CD), which are frequently associated with drug-resistant epilepsy and other neurological and mental disorders. 1,3-Bis-chloroethyl-nitrosurea (BCNU)-treated rats represent a model of CD due to the presence of histological alterations similar to those observed in human CD. BCNU is an alkylating agent that, administered at embryonic day 15 (E15), causes the loss of many cells destined to cortical layers; this results in cortical thinning but also in histological alterations imputable to migration defects, such as laminar disorganization and cortical and periventricular heterotopia. In the present study we investigated the genesis of heterotopia in BCNU-treated rats by labeling cortical ventricular zone (VZ) cells with a green fluorescent protein (GFP) expression vector by means of in utero electroporation. Here, we compared the migratory pattern and subsequent distribution of the GFP-labeled cells in the developing somatosensory cortex of control and BCNU-treated animals. To this aim, we investigated the expression of a panel of developmental marker genes which identified radial glia cells (Pax6), intermediate precursors cells (Tbr2), and postmitotic neurons destined to infragranular (Tbr1) or supragranular layers (Satb2). The VZ of BCNU-treated rats appeared disorganized since E18 and at E21 the embryos showed an altered migratory pattern: migration of superficial layers appeared delayed, with a number of migrating cells in the intermediate zone and some neurons destined to superficial layers arrested in the VZ, thus forming periventricular heterotopia. Moreover, neurons that reached their correct position did not extend their axons through the corpus callosum in the contralateral hemisphere as in the control, but toward the ipsilateral cingulated cortex. Our analysis sheds light on how a malformed cortex develops after a temporally discrete environmental insult.
Unit of Clinical Epileptology and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Ramona Frida
RF
Moroni
Francesca
F
Inverardi
Maria Cristina
MC
Regondi
Paolo
P
Pennacchio
Roberto
R
Spreafico
Carolina
C
Frassoni
D000818:Animals; D001369:Axons / Q000473:pathology*; D002330:Carmustine / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D018274:Electroporation / Q000379:methods; D005260:Female; D054220:Malformations of Cortical Development / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000473:pathology*; D054091:Periventricular Nodular Heterotopia / Q000139:chemically induced / Q000473:pathology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D002330:Carmustine