Brain plasticity and cellular mechanisms of epileptogenesis in human and experimental cortical dysplasia

Purpose: The cellular mechanisms that may contribute to epilepsy in resecte d human cortical dysplasia (CD) were compared with the in utero radiated ra t CD model. In human and rat focal hippocampal epilepsy, postsynaptic N-met hyl-D-aspartate receptors are up-regulated and presynaptic axon collaterals hyperinnervate them. We hypothesized that in both human and rat CD: (a) th e N-methyl-D-aspartate receptor subunits NR1 and NR2A/B would be increased and coassembled, and (b) aberrant axons would be in regions of CD. Methods: Tests for presynaptic and postsynaptic changes in human and rat CD included the following: (a) cytology, (b) immunocytochemistry, (c) coimmun oprecipitation, (d) double-labeled immunofluorescence, and (e) Timm histoch emistry of hippocampal mossy fibers. Within-patient comparisons were made b etween epileptic tissue, identified by subdural electroencephalographic sei zure onsets, and nonepileptic tissue remote from the focus but within the t herapeutic resection. Rats were radiated at embryonic day 17, and offspring were studied postnatally. Statistical comparisons were made against normal rats matched for age and tissue processing. Results: In focal CD patients, NR2A/B subunits and their coassemblies with NR1 were increased significantly more than for the remote nonepileptic cort ex. Confocal microscopy showed that NR1-NR2A/B colabeled single dysplastic neurons in both human and rat. In CD rats, mossy fibers innervated the anom alously oriented hippocampal neurons. Conclusions: Human epileptic CD exhibits a spectrum of abnormal cell orient ations and laminations that must require plastic axodendritic changes durin g development. These: altered circuits and receptors could account for the seizures and cognitive deficits found in patients with CD. The radiated rat CD model with cortical dyslaminations and NR2A/B subunit increases would a llow the development and testing of drugs targeted at only the NR2A/B subun it or at decoupling the NR1-NR2 coassembly, which could provide a specific antiepileptic drug for dysplastic circuits without inducing general depress ion of all brain neurons.