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Title: Analysis of NMDA receptor regulated gene expression
Author: Begg, Alison Jane
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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Mutation of two NMDA receptor complex proteins, PSD95 and SynGAP, results in altered phenotypes in NMDA dependent phenomena. As components of the receptor complex, necessary for NMDA mediated signalling, mutation of these proteins may alter pathways that regulate gene expression. Affymetrix microarray analysis of RNA from PSD95-/- forebrain and SynGAP-/- hippocampi, compared to wildtype samples, revealed significant changes, greater than 1.5 fold, in a limited numbers of genes. Of the 12000 transcripts analysed 0.22% were significantly altered in PSD95 mutant tissue and 0.35% were changed in SynGAP mutant tissue. The genes altered in each genotype were distinct, apart from an overlap of 3 genes that were found similarly down regulated in PSD95-/- forebrain and SynGAP-/- hippocampi. These 3 genes, c-fos, nur77 and egr2, are activity dependent and are regulated, in part, through the NMDA receptor. It is possible that changes in gene expression may underlie the electrophysiological and behavioural phenotypes seen PSD95-/- and SynGAP+/- animals. It is likely that the genes altered in each of the mutants represent a subset of the genes regulated by NMDA receptor signalling. To get an understanding of the complete set of genes regulated by the NMDA receptor complex and in vitro method of NMDA receptor stimulation was sought. A primary cultured neuron system was used, allowing NMDA receptor activity to be manipulated by the pharmacological treatment of the culture medium. NMDA and bicuculline treatment of primary cultured cortical neurons proved ineffective methods of inducing activity dependent genes as measured by cfos expression. However, AP5 treatment of primary cultured neurons decreased activity dependent gene expression. Electrophysiological analysis of the cultures revealed that bicuculline treatment had no significant effect on culture activity, where as AP5 treatment caused a significant decrease in neuronal activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available