Characterization of heterotopic cell clusters in the hippocampus of rats exposed to methylazoxymethanol in utero

Cortical disorganization represents one of the major clinical findings in m any children with medically intractable epilepsy. To study the relationship between seizure propensity and abnormal cortical structure, we have begun to characterize an animal model exhibiting aberrant neuronal clusters (hete rotopia) and disruption of cortical lamination. In this model, exposing rat s in utero to the DNA methylating agent methylazoxymethanol acetate (MAM; e mbryonic day 15) disrupts the sequence of normal brain development. In MAM- exposed rats, cells in hippocampal heterotopia exhibit neuronal morphology and do not stain with immunohistochemical markers for glia. In hippocampal slices from MAM-exposed animals, extracellular field recordings within hete rotopia suggest that these dysplastic cell clusters make synaptic connectio ns locally (i.e. within the CA1 hippocampal subregion) and also make aberra nt synaptic contact with neocortical cells. Slice perfusion with bicucullin e or 4-aminopyridine leads to epileptiform activity in dysplastic cell clus ters that can occur independent of input from CA3. Taken together, our find ings suggest that neurons within regions of abnormal hippocampal organizati on are capable of independent epileptiform activity generation, and can pro ject abnormal discharge to a broad area of neocortex, as well as hippocampu s. (C) 2000 Elsevier Science B.V. All rights reserved.