Glutamate receptor mechanisms in human epileptic dysplastic cortex.
Developmental disorders of neuronal migrations in the human brain are referred to as 'cortical dysplasia', and current knowledge of cortical dysplasia is limited to varied pathologic descriptions which lack specific investigations of glutamate receptor mechanisms. In this study, immunocytochemistry was used to study the expressions of glutamate receptor subunit proteins for NMDAR2A/B, NMDAR1 and AMPA Glu-R2/3 in human brain resected for intractable epilepsy associated with cortical dysplasia. Seventeen patients were studied with batch-matched glutamate subunit reagents on adjacent 30-microm sections. The most striking microscopic abnormalities identified in cresylecht violet stains were cortical dyslaminations, disoriented neurons, and unexpectedly, very dark Nissl body staining of those dysplastic neurons. NMDAR2A/B intensely labeled dysplastic neurons, showing staining in both the cell bodies and dendritic profiles. However, non-dysplastic neurons were not immunoreactive to NMDAR2A/B. Dysplastic neurons were also labeled by antibodies selective to NMDAR1. Both dysplastic neurons and non-dysplastic neurons were immunoreactive to AMPA GluR2/3. Our results suggest that the epileptic hyperexcitability of dysplastic cortical regions may result, at least in part, from the heteromeric coassembly and expressions of NMDAR2A/B subunits with selectively expressed NMDAR1 splice variants in dysplastic neurons. AMPA receptors are probably also essential but not sufficient to explain the 'epileptic' properties of these dysplastic neurons. A longer, detailed report of some of these findings have been previously published (Ying et al., 1998. J. Neuropathol. Exp. Neurol. 57, 47-62).
Department of Neurosciences, The Cleveland Clinic Foundation, OH 44195, USA. babbt@cesmtp.ccf.org
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Babb
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Ying
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Hadam
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Penrod
D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D002540:Cerebral Cortex / Q000002:abnormalities / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism* / Q000601:surgery; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*
D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104723:glutamate receptor ionotropic, AMPA 3; C104722:glutamate receptor ionotropic, AMPA 2