The NMDA receptor NR2B subunit contributes to epileptogenesis in human cortical dysplasia.
Cortical dysplasia (CD) is often associated with pharmacoresistant epilepsy. Previous studies showed increased expression of the NMDA receptor subunit NR2B in dysplastic and epileptic human neocortex. We tested the hypothesis that differential increase of NR2B constitutes an epileptogenic mechanism in humans. Dysplastic neocortex and lateral temporal lobe regions resected for treatment of pharmacoresistant seizures were processed for electrophysiological, histological, and immunocytochemical studies. Assignment to the "dysplastic" (n = 8) and "non-dysplastic" (n = 8) groups was based on histology. Neurons in "dysplastic" samples differentially stained for NR2B. Western blot (n = 6) showed an immunoreactive band for NR2B in three out of four "dysplastic" samples. Epileptiform field potentials (EFP) were elicited in vitro by omission of magnesium from the bath. EFP in "dysplastic" slices were characterized by multiple afterdischarges, occurring at a significantly higher repetition rate than EFP in non-dysplastic slices. The NR2B-specific NMDA receptor inhibitor ifenprodil (10muM) suppressed EFP in dysplastic slices. In non-dysplastic slices, burst repetition rate did not change with ifenprodil application. In both dysplastic and non-dysplastic slices, EFP were suppressed by a non-specific NMDAR antagonist (APV) or AMPA receptor antagonist (CNQX). These results provide additional evidence that the differential expression of NR2B in dysplastic human neocortex may play a role in the expression of in-situ epileptogenesis in human CD. NR2B may constitute a target for new diagnostic and pharmacotherapeutic approaches.
Möddel
Gabriel
G
Department of Neurology, The Cleveland Clinic Foundation, OH 44195, USA. gabriel.moeddel@gmx.de
Jacobson
Berit
B
Ying
Zhong
Z
Janigro
Damir
D
Bingaman
William
W
González-Martínez
Jorge
J
Kellinghaus
Christoph
C
Prayson
Richard A
RA
Najm
Imad M
IM
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003344:Cortical Synchronization / Q000187:drug effects; D004828:Epilepsies, Partial / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D019579:Neocortex / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism* / Q000601:surgery; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D016037:Single-Blind Method; D018709:Statistics, Nonparametric
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C010739:ifenprodil