Abstracts

Methylazoxymethanol (MAM) injection in rats produces a model of cortical dysplasia consisting of intrahippocampal and/or periventricular heterotopia. Previously we showed that CA1 heterotopic cells are integrated into hippocampal and cortical circuits. In the present study, we have compared heterotopic and normal CA1 hippocampus with respect to initiation and propagation of epileptiform discharges. We hypothesized that the heterotopia would be the site of discharge initiation when the slice was challenged with an epileptogenic agent. Pregnant female Spargue-Dawley rats were injected with MAM (25 mg/kg, i.p.) at E15. Acute hippocampal brain slices were obtained from MAM-exposed offspring at P21-P35. Simultaneous field recordings were obtained from the CA1 heterotopia and the neighboring normal CA1 subfield. Spontaneous activity was elicited by adding the GABA[sub]A[/sub]-receptor antagonist, bicuculline methiodide (50[sub][micro][/sub]M), and elevating the K⁺-concentration (from 3 to 5 mM) in the bathing solution. A bipolar electrode was placed in the stratum radiatum near CA3 to stimulate Schaffer collaterals. A single MAM injection consistently produced hippocampal (CA1) heterotopia in the exposed offspring. Bicuculline application with K⁺-concentration elevation led to spontaneous synchronized epileptiform events (multiple population spikes) in the heteropia and neighboring CA1. Onset of spontaneous events, relative to the time of bicuculline introduction, was indistinguishable between CA1 and the heterotopia. Epileptiform bursts were often followed by large negative shifts, with or without after-discharge; after-discharge spikes could occur in the heterotopia electrode without concurrent spiking in normal CA1. In most cases, spontaneous events in CA1 preceded the discharges in the heterotopia (independent of the location of the heterotopia within the CA1 subfield). When responses were evoked by the stimulating electrode, however, the recording electrode closer to the stimulus site (whether in normal CA1 or in the heterotopia) showed the earlier onset of discharge. Our data suggest that: 1) spontaneous epileptiform events arise in the hippocampus, not the heterotopia; 2) the heterotopia is capable of independent epileptiform spiking; and 3) there is a powerful synaptic input from the normal hippocampus to the heterotopia that usually drives epileptiform discharges in the heterotopia. (Supported by NIH grant NS18895 (PAS))