Epileptogenicity correlated with increased N-methyl-D-aspartate receptor subunit NR2A/B in human focal cortical dysplasia

Purpose: Human cortical dysplasia (CD) is a frequent cause of medically int ractable focal epilepsy. The neurotransmitter mechanisms of epileptogenicit y in these lesions have been attributed to changes in various glutamate rec eptor subtypes. Increased N-methyl-D-aspartate (NMDA) receptor (NR) 2A/B co assembled with NR1 subunits has been shown in focal epileptic CD, The purpo se of this study is to correlate in situ CD epileptogenicity and the expres sion of various glutamate receptor subtypes. Methods: The histopathological, morphological, and immunocytochemical findi ngs in cortical tissue resected from five patients with medically intractab le epilepsy and CD were correlated with electroencephalographic data record ed from subdural grids. The NMDA antibodies identified subunits NR1 (splici ng variants 1a, 1b, 2a, and 2b) and NR2A/B. Results: Epileptogenic specimens displayed the following common features: ( a) widespread histological abnormalities of horizontal and columnar dyslami nation, neurons with inverted polarity, and more extensive dendritic change s; (b) significantly higher NR2A/B immunoreactivity in both the dysplastic somata and all their dendritic processes; and (c) no statistically signific ant change in NR1 subunit expression but a more pronounced staining of the epical dendrites in highly epileptogenic cortex. These abnormalities were e ither absent or minimal in resected specimens that did not show evidence of severe in vivo epileptogenicity. Conclusion: These studies provide direct evidence for a major contribution of the NR2A/B subunit in CD-induced epileptogenicity.