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

From the Departments of Neurology (Dr. Crino and R. White) and Neurosurgery (Drs. Duhaime and Baltuch), and the Penn Epilepsy Center (Drs. Crino and Baltuch), University of Pennsylvania School of Medicine; and the Children’s Hospital of Philadelphia (Dr. Duhaime), PA.

Address correspondence and reprint requests to Dr. Peter B. Crino, Department of Neurology, University of Pennsylvania, 3 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19104; e-mail: crinop{at}mail.med.upenn.edu

OBJECTIVE: 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 -aminobutyric acid A receptor (GABA_AR) subunits is distinct in dysplastic and heterotopic neurons and that changes in receptor gene expression could be defined in a cell-specific pattern.

METHODS: 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_AR_1–6, and -Rß_1–3 subunit cDNAs. The relative hybridization intensities of each mRNA-cDNA hybrid were quantified by phosphorimaging.

RESULTS: GluR, NR, and GABA_AR subunit mRNA expression did not differ between control neurons and nondysplastic epilepsy specimens. Expression of GluR₄, NR_2B, and NR_2C subunit mRNA was increased, and NR_2A and GABA_ARß₁ subunit mRNA was decreased in dysplastic compared with pyramidal and heterotopic neurons. In contrast, GABA_AR₁, -R₂, and -Rß₂ as well as GluR₁ mRNA levels were reduced in both dysplastic and heterotopic neurons.

CONCLUSIONS: Differential expression of GluR, NR, and GABA_AR 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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