Abstracts

In the rat freeze-lesion model of microgyria, there is a delay to onset of epileptogenesis and an apparent recovery that occurs selectively in animals lesioned on the day of birth as opposed to the first postnatal day after birth (P1, Jacobs 1999, JNP, 81:159). In order to investigate mechanisms of hyperexcitability onset and recovery over an expanded period of development, we have created a model of microgyria in the more altricial ferret. An important difference between P1 and P0 in the rat is the presence of a greater number of layer IV neurons within the cortical plate. Anatomical experiments have shown that thalamic axons innervate the paramicrogyral cortex heavily, where layer IV cells are present while avoiding the microgyrus (Jacobs 1999 Epilepsy Res, 36: 165; Rosen 2000 JCN, 418: 423). Hyperinnervation of paramicrogyral neurons by excitatory afferents has also been demonstrated, suggesting this may contribute to hyperexcitability that is selectively found adjacent to the microgyrus. We hypothesize that the greater proportion of layer IV neurons lesioned, the more epileptogenic the adjacent cortex will be and the less likely are the chances of recovery. We have tested this by altering the lesion day for the ferret and testing for the presence of epileptiform activity. Transcranial freeze lesions were made in ferrets aged 0, 3, or 6 days after birth, by applying a rectangular probe 2 X 5 mm, at [ndash]70[deg]C to the skull overlying occipital cortex for 6-10 seconds. Coronal slices were prepared from occipital cortex in ferrets aged 30 to 70 days. Field potential recordings were made in superficial layers in response to deep layer stimulation from 4-12 locations in each slice. Slices were subsequently fixed in 4% paraformaldehyde, resectioned at 60 [mu]m, and stained with cresyl violet. Nissl-stained sections showed that at least one additional sulcus was created in freeze-lesioned ferrets. Microgyri surrounding the sulcus appeared similar to those in rats, having 4 layers and being bordered by a cell-sparse column of tissue. Heterotopia bordering the microgyrus were common in P3 lesioned cortex, while large ectopia above the pia were found in P6 lesions. In slices from control (unlesioned) ferrets, field potentials contained an early sharp negativity graded with intensity followed by a smaller amplitude, long lasting (typically 400 msec) negativity (N[sub]2[/sub]). Qualitative inspection showed that the amplitude of the N[sub]2[/sub] component of the field was enhanced in slices from lesioned animals. Long latency events having characteristics of interictal-like epileptiform activity were seen in 100% of slices from P6 lesions, 10% of P3 lesions, 0% of P0 lesions, and 0% of controls (n = 8, 20, 4, and 24 respectively). These results show that a lesion early in development produces a similar pattern of histopathology in gyral and lissencephalic cortex. The ferret model of microgyria will be particularly useful in studying mechanisms of epleptogenesis onset and recovery. (Supported by NIH grant NS045901 from the NINDS)