Epileptogenicity Correlated with Increased N‐Methyl‐d‐Aspartate Receptor Subunit NR2A/B in Human Focal Cortical Dysplasia

Abstract

Summary:Purpose: Human cortical dysplasia (CD) is a frequent cause of medically intractable focal epilepsy. The neurotransmitter mechanisms of epileptogenicity in these lesions have been attributed to changes in various glutamate receptor subtypes. Increased N-methyh-aspartate (NMDA) receptor (NR) 2A/B coassembled with NRI subunits hag been shown in focal epileptic CD. The purpose of this study is to correlate in situ CD epileptogenicity and the expression of various glutamate receptor subtypes.Methods: The histopathological, morphological, and immunocytochemical findings in cortical tissue resected from five patients with medically intractable epilepsy and CD were correlated with electroencephalographic data recorded from subd u d grids. The NMDA antibodies identified subunits NRl (splicing variants la, lb, 2a, and 2b) and NR2A/B.Results: Epileptogenic specimens displayed the following common features: (a) widespread histological abnormalities of horizontal and columnar dyslamination, neurons with inverted polarity, and more extensive dendritic changes; (b) significantly higher NR2A/B immunoreactivity in both the dysplastic somata and all their dendritic processes; and (c) no statistically significant change in NR1 subunit expression but a more pronounced staining of the apical dendrites in highly epileptogenic cortex. These abnormalities were either 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. Key Words: Cortical dysplasia-EpilepsyReceptor-NMDA.In surgical series, cortical dysplasia (CD) is one of the most frequent causes of medically intractable focal epilepsy after hippocampal sclerosis, but CD carries a worse prognosis for seizure-free outcome (1,2). In an increasing number of patients with childhood-onset or early adult-onset epilepsy, magnetic resonance imaging (MRI) can now show the developmental nature of epileptogenic lesions by precisely defining gyral anatomy and gray-white matter junction (3). Nevertheless, the cellular mechanisms underlying CD epileptogenicity and the roles of excitatory amino acid receptors in the expression of the seizures remain largely unknown. Recent Accepted May 24, 2000Address correspondence and reprints requests to Dr. Imad M. Najm, Section of Epilepsy, 9500 Euclid Avenue, Desk S5 I , Cleveland, OH 44195, U.S.A. E-mail: najmi@ccf.org studies described the cellular morphological changes and a differential expression of various subtypes of glutamate receptors in human CD lesions associated with intractable seizures (45). We have shown diffuse morphological changes and increases in N-methyl-D-aspartate (NMDA) receptor (NR) subunits 2A/B in areas of CD resected from patients with intractable seizures (5). Moreover, Spreafico et al. (4) recently reported an increase in the immunoreactivity of the a-amino-3-hydroxy-5-niethyl-4-isonazolepropionic acid (AMPA) glutamate receptor subunits GluR2/3 and...

The pathology of magnetic-resonance-imaging-negative epilepsy

“…[28][29][30] In addition to the accurate definition, delineation of the boundaries of type I focal cortical dysplasia is also difficult, as the microscopically dysplastic lesion may extend well beyond the margins defined by the MRI-visible abnormality (in MRIpositive cases), [30][31][32] even with the use of highresolution dedicated epilepsy MRI protocols and review of the images by expert neuroradiologists. 26,32 Our finding of MRI-negative patients with hippocampal sclerosis is also consistent with previous literature that up to 30% of patients with hippocampal sclerosis may have normal findings on conventional MRI. 33 Surgical outcome of MRI-negative patients can be hard to determine due to heterogeneity of patient populations, surgical techniques, follow-up time, and outcome definition in the literature.…”

Subtype-selective antagonism of N-methyl-d-aspartate receptor ion channels by synthetic conantokin peptides

“…Another study has suggested a link between the NR2A level and the symptomatic progression of this disease (Ali and Levine, 2006). An important role has been ascribed to NR2A/B subunits in human cortical dysplasia-induced epilepsy (Najm et al, 2000). The NR2B subtype has been implicated in Parkinson's disease (Nash et al, 1999) and in the mediation of nociception (Tan et al, 2005).…”

The influence of lesion volume, perilesion resection volume, and completeness of resection on seizure outcome after resective epilepsy surgery for cortical dysplasia in children

“…There is some evidence to suggest that balloon cells display intrinsic hyperexcitability, possibly because of a modification of N-methyl-d-aspartate receptors or decreased sensitivity of the γ-aminobutyric acid A receptors in these pacemaker cells. 10,18,19,31,32 In more diffuse cortical dysplasia, there may be abnormal connectivity of the cellular aggregate, which is associated with reorganization of cortical circuitry, and axons that would normally project out of the epileptic zone may also be interrupted and instead make excitatory synapses locally. These recurrent excitatory connections may cause feed-forward connectivity loops that drive the excitatory and consequent epileptic process.…”