Abstracts

Cortical malformations are one of the most common causes of medically intractable epilepsy. One of the more common malformations is polymicrogyria (PMG), where up to 80% of patients have epilepsy. The underlying mechanisms responsible for this high incidence of epilepsy are not known, nor is it known if epileptic regions of neocortex differ between patients with PMG and patients with non-lesional neocortical epilepsy. Recently, we used a functional genomic strategy to identify a small group of activity-depdnent genes are induced in neocortical epileptic foci, regardless of the underlying cause. Here, we hypothesize that both common and as well as unique patterns of gene expression can be identified in children with PMG compared to patients with non-lesional neocortical epilepsy. Localization of these induced genes can identify neuronal populations involved human epilepsy associated with malformations., Electrically mapped neocortical tissue was obtained from 8 children with intractable epilepsy (4 with PMG, and 4 with gliosis) who underwent a two-stage surgical resection. The seizure onset region and a nearby area without spontaneous epileptiform activity as a [quot]control[quot] were compared by histology, real-time qPCR, and Agilent genome wide microarrays. Genes identified as differentially expressed were characterized further by in situ hybridization to identify populations of activated neurons., Despite a marked difference in tissue histology between PMG patients and those with gliosis, there was a remarkably similar pattern of gene induction at regions of seizure onset and maximal interictal spiking. Patients without malformations expressed these activity-dependent genes predominantly in normal-appearing layers II-IV pyramidal neurons. In patients with PMG, these same genes were also restricted to layer II-IV neurons, in highly epileptic regions directly adjacent to thickened layer I regions in the polymicrogyri. In addition to common gene expression changes, we also identified genes uniquely altered in PMG neocortex that could underlie some of the morphollgical features of this malformation., Results genomic studies of PMG suggest that similar molecular pathways are activated in PMG as in other non-lesional forms of neocortical epilepsy, however, the expression of some of these activity-dependent genes in PMG localize to neurons directly adjacent to malformations. In addition, there are unique patterns of gene expression in PMG that are likely to relate directly to the malformation., (Supported by: 1. NIH NINDS R01 NS45207.; 2. Postdoctoral fellowships from the Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA; 3.Japan research foundation for clinical pharmacology, Tokyo, Japan.)