Mechanisms of abnormal development in an injury-induced model of cortical malformations

Malformations of cortical development are frequently associated with severe neurological disorders such as autism, mental retardation, and pediatric cases of intractable epilepsy. Current studies have focused on understanding mechanisms underlying epileptogenesis in these conditions. However, a more general and far-reaching question of how a malformed brain develops remains unanswered. The overall aim of this dissertation was to characterize defects in cortical development that occur in the teratogen-induced model of cortical dysplasia i.e., prenatal methylazoxymethanol (MAM) exposure in the rat. The results established that nodular heterotopias in the hippocampus of MAM-exposed rats arise early in the postnatal period, following a loss of cell adhesion and increased cell death at the cortico-hippocampal junction. In the embryonic brain, we observed a break down of the radial glial scaffold and disruption of prenatal architecture (including elements such as the cortical plate and ventricular zone). In addition, the marginal zone, an already established region, appeared disorganized. The unexpected disorganization of the marginal zone could result from an acute loss of stromal-derived factor-1 (SDF-1). Our results demonstrated that SDF-1 was sufficient and necessary for reelin-(+) cells to localize to the meningeal surface in the MAM brain in vitro . This finding revealed that a global insult (i.e., teratogen exposure) can result in a specific alteration of a soluble factor critical to neurodevelopment (i.e., decreased SDF-1 in the meninges). The normal marginal zone also required SDF-1 for structural maintenance since blocking SDF-1 activity in vitro and in vivo resulted in marginal zone disorganization. From these anatomical studies in MAM-exposed rats, we uncovered specific molecules and steps in the process of abnormal brain development. These findings, at least in some cases, are similar to what was observed in cortical dysplastic tissue obtained from patients with epilepsy e.g., a disruption of the superficial layer (MZ in the MAM-exposed brain and layer I tissue from FCD patients). This works supports the use of animal models to uncover fundamental mechanisms related to how a malformed brain develops. These findings in the MAM-exposed rat brain could provide insight into the processes taking place in patients with malformations of cortical development.