Article

Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia.

Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Neurology (Impact Factor: 8.3). 05/2001; 56(7):906-13. DOI: 10.1212/WNL.56.7.906
Source: PubMed

ABSTRACT Focal cortical dysplasia is characterized by disorganized cortical lamination, dysplastic and heterotopic neurons, and an association with epilepsy. The contribution that dysplastic and heterotopic neurons make to epileptogenesis in focal cortical dysplasia is unknown and the phenotype of these cells may be distinct. The authors hypothesized that the expression of genes encoding glutamatergic (glutamate [GluR] and N-methyl-D-aspartate NMDA receptors [NR]) and gamma-aminobutyric acid A receptor (GABA(A)R) subunits is distinct in dysplastic and heterotopic neurons and that changes in receptor gene expression could be defined in a cell-specific pattern.
Single immunohistochemically labeled dysplastic and heterotopic neurons were microdissected from human focal cortical dysplasia specimens obtained during epilepsy surgery. Pyramidal neurons were microdissected from postmortem control cortex and from temporal cortex without dysplasia resected during temporal lobectomy. Poly (A) messenger RNA (mRNA) from single neurons was amplified, radiolabeled, and used to probe complementary DNA (cDNA) arrays containing GluR(1-6), NR(1A,1B), NR(2A-D), and GABA(A)Ralpha(1-6), and -Rbeta(1-3) subunit cDNAS: The relative hybridization intensities of each mRNA-cDNA hybrid were quantified by phosphorimaging.
GluR, NR, and GABA(A)R subunit mRNA expression did not differ between control neurons and nondysplastic epilepsy specimens. Expression of GluR(4), NR(2B), and NR(2C) subunit mRNA was increased, and NR(2A) and GABA(A)Rbeta(1) subunit mRNA was decreased in dysplastic compared with pyramidal and heterotopic neurons. In contrast, GABA(A)Ralpha(1), -Ralpha(2), and -Rbeta(2) as well as GluR(1) mRNA levels were reduced in both dysplastic and heterotopic neurons.
Differential expression of GluR, NR, and GABA(A)R mRNA in dysplastic and heterotopic neurons demonstrates cell specific gene transcription changes in focal cortical dysplasia. These results suggest that dysplastic and heterotopic neurons may be pharmacologically distinct and make differential contributions epileptogenesis in focal cortical dysplasia.

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    • "They found changes in GABA A receptors with reorganization of specific receptor subtypes in some cells and interneurons. In addition, Crino et al. (2001) found different patterns of GABA A receptor subunit expression in cortical dysplasia. Using immunohistochemistry, the authors observed a decrease in the expression of the b1 subunit in dysplastic neurons compared with pyramidal and heterotopic neurons. "
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    • "Previous studies of GABA A receptor expression and function in focal cortical dysplasia have produced varying results. Single-cell PCR studies of dysplastic and heterotopic neurons in resected tissue from older children and adults with FCD revealed a reduction in α 1 subunit mRNA (Crino et al., 2001). However, in an immunohistochemical study which included two adults with cortical dysplasia, no difference in α 1 immunoreactivity was identified (Loup et al., 2000). "
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    • "Whatever the underlying cause for focal MCD, there are clear neurochemical changes that occur as secondary or corollary effects in relation to the pathologic defect. For example, several studies have demonstrated alterations in glutamate [N-methyl-D-aspartate (NMDA), a-amino-3- hydroxyl-5-methyl-4-isoxazole-propionate (AMPA), and mGlu receptors] and/or c-aminobutyric acid (GABA) receptor subunits in focal cortical dysplasia (Crino et al., 2001; Aronica et al., 2003; Andre et al., 2004). Translational interpretation of these results has proven to be complex . "
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