Abstracts

RATIONALE: Cortical dyplasia is an important cause of epilepsy. Experimental models of cortical dysplasia that share features with human dysplasia may help elucidate the underlying mechanism of epilepsy in this condition. We treated rats with a single dose of BCNU in utero in order to generate dysplastic neocortex. We found that the resulting cortex displays histological and physiological features similar to epileptogenic dysplastic cortex in humans. METHODS: Pregnant rats received IP injections of BCNU between days E14 and E17. The rat pups were perfused and the brains processed for histology at P0-P60. Field recordings and whole cell recordings were also obtained from neocortical slices (400 um) made from treated rats at P7-P70. In addition, total RNA was prepared from P60 brain slices and quantitative relative RT-PCR was performed for the immediate early genes (IEGs), c-fos and c-jun. RESULTS: Histological data shows that the dysplastic cortex has disruption of the normal lamination pattern as well as a significant population of hypertrophic neurons in layers 4/5. Similar cellular changes have been observed in some human cortical dysplasias. Under conditions of partial GABAA blockade, dysplastic cortex demonstrates increased excitability with large numbers of synchronized neuronal discharges compared to control. RT-PCR demonstrates that there is a higher level of basal and induced c-fos expression in the dysplastic cortex compared to control suggesting enhanced neuronal activity. CONCLUSIONS: In utero BCNU exposure produces a model of cortical dysplasia that displays many features of epileptogenic neocortex. We plan to further investigate the model in order to understand better the mechanism of epilepsy in dysplastic cortex. SUPPORT: This work was supported by NIH grant NS21223 and a grant from the Patterson Trust.