Abstracts

Cortical dysplasias (CD) frequently cause pharmacoresistant epilepsy. Enhancement of NR2B subunit of the NMDA receptor (NMDAR) contributes to hyperexcitability in a rat model of CD [1]. Correlation of ECoG recordings with immunocytochemical (ICC) stains of resected tissue suggest that these findings are also relevant for humans [2]. The goal of this study was to test the hypotheses that: 1) increased expression of NR2B in human CD correlates with increased epileptiform field potentials (EFP) generation [italic]in-vitro[/italic], and that 2) application of the NR2B-specific NMDAR blocker ifenprodil suppresses EFP generated by dysplastic human cortex, whereas it has less effect on normal cortex.
Human neocortical slices were superfused with Mg²⁺-free media to elicit EFP. 10 [mu]M ifenprodil was added to the bath for 1 h, followed by washout. Field potentials were recorded and EFP frequency (F), burst integral (BI), and activity index (AI=F*BI) calculated. After recording, slices were fixed in paraformaldehyde for histological processing. On the basis of histology, cases were classified as dysplastic or normal. Data are given as mean +- SEM.
ICC stains of control and dysplastic tissue showed differential NR2B expression in dysplastic tissue but not in controls. In dysplastic cortex (n=2) EFP occurred at F=1.6 +- 1.2 min^-1 with BI=3110 +- 2771 [mu]Vs and AI=4816 +- 723 [mu]Vs*min^-1. 10 [mu]M ifenprodil resulted in complete suppression of EFP (AI=1.87 [mu]Vs*min^-1 [-99.9 %]). Controls (n=3) displayed EFP occurring at F=1.4 +- 0.2 min^-1, with BI=313 +- 155 [mu]Vs and AI=429 +- 185 [mu]Vs*min^-1. Application of ifenprodil reduced AI to 90.81 +- 26 [mu]Vs*min^-1 (-79 %). Thus, EFP in dysplastic neocortex had 10fold larger BI and AI, compared to EFP in controls. Ifenprodil caused complete suppression of EFP in dysplastic cortex (reduction of AI [gt] 99.9 %). In controls, AI was only reduced by 79 %.
The results suggest that: 1) CD lesions are hyperexcitable [italic]in-vitro[/italic] and thus are likely to be epileptogenic [italic]in vivo[/italic], and 2) enhanced expression of NR2B contributes to epileptogenicity in humans. This has implications for diagnostics and therapies for patients with intractable epilepsy. NR2B could constitute a target for functional imaging. Substances selectively blocking neuronal activity in epileptogenic regions are a promising perspective for the medical treatment of epilepsy.
References:
[1] Defazio A, Hablitz JJ: Alterations in NMDA receptors in a rat model of cortical dysplasia. [italic]J Neurophysiol[/italic] (2000): 315-321
[2] Najm I, Ying Z, Babb, T, Mohamed A, Hadam J, LaPresto E, Wyllie, E, Kotagal P, Bingaman W, Foldvary N, Morris H, Lueders HO: NMDA receptor 2A/B subtype differential expression in human cortical dysplasia: correlation with in-situ epileptogenicity. [italic]Epilepsia[/italic] (2000): 971-976
[Supported by: Zentrum fur Innovative Medizinische Forschung (IMF) of University of Muenster, Germany]