Initiation and spread of epileptiform discharges in the methylazoxymethanol acetate rat model of cortical dysplasia: Functional and structural connectivity between CA1 heterotopia and hippocampus/neocortex

Neuronal migration disorders (NMDs) are often associated with medically intractable epilepsy. In utero injection of methylazoxymethanol acetate into pregnant rats gives rise to dysplastic cell clusters (“heterotopia”) in hippocampus (and nearby regions), providing an animal model of NMD. In the present study, we have examined the structural and functional integration of hippocampal heterotopic cells into circuits that link the heterotopia with surrounding “normal” brain. Bi-directional morphological connectivity between the heterotopia and hippocampus/neocortex was demonstrated using the neurotracer, biotinylated dextran amine. Single cell recordings in hippocampal slices showed that heterotopia neurons form functional connections with the surrounding hippocampus and neocortex. However, simultaneous field recordings from the CA1 heterotopia, normotopic hippocampus, and neocortex indicated that epileptiform discharges (spontaneous events seen in slices bathed with high [K+]o and bicuculline) were rarely initiated in the heterotopia (although the heterotopia was capable of generating epileptiform discharges independently of normal brain regions). Further, in most of the experiments, the aberrant connectivity provided by CA1 heterotopia failed to function as a “bridge” for epileptiform discharges to propagate directly from low-threshold hippocampus to neocortex. These data do not support the hypothesis that NMDs (heterotopic cell populations) serve as a focus and/or trigger for epileptiform activity, and/or facilitate propagation of epileptiform events.