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.