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Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers

2001; Wiley; Volume: 49; Issue: 1 Linguagem: Inglês

10.1002/1531-8249(200101)49

1531-8249

Ricarda White, Yue Hua, Bernd W. Scheithauer, David R. Lynch, Elizabeth P. Henske, Peter B. Crino,

Wnt/β-catenin signaling in development and cancer

Annals of NeurologyVolume 49, Issue 1 p. 67-78 Original Article Selective alterations in glutamate and GABA receptor subunit mRNA expression in dysplastic neurons and giant cells of cortical tubers Ricarda White BA, Ricarda White BA PENN Epilepsy Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PASearch for more papers by this authorYue Hua MD, Yue Hua MD PENN Epilepsy Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PASearch for more papers by this authorBernd Scheithauer MD, Bernd Scheithauer MD Division of Anatomic Pathology, Mayo Clinic, Rochester, MNSearch for more papers by this authorDavid R. Lynch MD, PhD, David R. Lynch MD, PhD PENN Epilepsy Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PASearch for more papers by this authorElizabeth Petri Henske MD, Elizabeth Petri Henske MD Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PASearch for more papers by this authorPeter B. Crino MD, PhD, Corresponding Author Peter B. Crino MD, PhD [email protected] PENN Epilepsy Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PADepartment of Neurology, University of Pennsylvania, 3 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19104Search for more papers by this author Ricarda White BA, Ricarda White BA PENN Epilepsy Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PASearch for more papers by this authorYue Hua MD, Yue Hua MD PENN Epilepsy Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PASearch for more papers by this authorBernd Scheithauer MD, Bernd Scheithauer MD Division of Anatomic Pathology, Mayo Clinic, Rochester, MNSearch for more papers by this authorDavid R. Lynch MD, PhD, David R. Lynch MD, PhD PENN Epilepsy Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PASearch for more papers by this authorElizabeth Petri Henske MD, Elizabeth Petri Henske MD Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PASearch for more papers by this authorPeter B. Crino MD, PhD, Corresponding Author Peter B. Crino MD, PhD [email protected] PENN Epilepsy Center and Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PADepartment of Neurology, University of Pennsylvania, 3 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19104Search for more papers by this author First published: 16 January 2001 https://doi.org/10.1002/1531-8249(200101)49:1 3.0.CO;2-LCitations: 117Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract The molecular pharmacologic basis of epileptogenesis in cortical tubers in the tuberous sclerosis complex is unknown. Altered transcription of genes encoding glutamatergic and γ-aminobutyric acid (GABA)-ergic receptors and uptake sites may contribute to seizure initiation and may occur selectively in dysplastic neurons and giant cells. Arrays containing GABA A (GABAAR), GluR, NMDA receptor (NR) subunits, GAD65, the vesicular GABA transporter (VGAT), and the neuronal glutamate transporter (EAAC1) cDNAs were probed with amplified poly (A) mRNA from tubers or normal neocortex to identify changes in gene expression. Increased levels of EAAC1, and NR2B and 2D subunit mRNAs and diminished levels of GAD65, VGAT, GluR1, and GABAAR α1 and α2 were observed in tubers. Ligand-binding experiments in frozen tuber homogenates demonstrated an increase in functional NR2B-containing receptors. Arrays were then probed with poly (A) mRNA from single, microdissected dysplastic neurons, giant cells, or normal neurons (n = 30 each). Enhanced expression of GluR 3, 4, and 6 and NR2B and 2C subunit mRNAs was noted in the dysplastic neurons, whereas only the NR2D mRNA was upregulated in giant cells. GABAAR α1 and α2 mRNA levels were reduced in both dysplastic neurons and giant cells compared to control neurons. Differential expression of GluR, NR, and GABAAR mRNAs in tubers reflects cell-specific changes in gene transcription that argue for a distinct molecular phenotype of dysplastic neurons and giant cells and suggests that dysplastic neurons and giant cells make differential contributions to epileptogenesis in the tuberous sclerosis complex. Ann Neurol 2001;49:67–78 References 1 Van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277: 805–808. 2 Consortium ECTS. 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