Identification and characterisation of novel candidate genes for schizophrenia

Marquet, Anne (2006) Identification and characterisation of novel candidate genes for schizophrenia. PhD thesis, University of Glasgow.

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Abstract

Schizophrenia is a severe and debilitating mental disorder that affects 1% of the population. Clinical symptoms usually show at late adolescence or early adulthood and include a constellation of delusions, hallucinations, decreased motivation and impaired executive functions. The aetiology of schizophrenia remains unclear but like most psychiatric disorders it is classified as complex in origin, resulting from an interplay of genetic, developmental and environmental factors. Recent intensive research has enabled the identification of susceptibility genes for schizophrenia, giving interesting insights into its pathophysiology. However, schizophrenia is such an heterogeneous and polygenic disease that more genes will have to be discovered, not only to help further towards a better understanding of the molecular mechanisms associated with schizophrenia but also to lead to the identification of novel pharmacological targets. A global transcriptome screen to identify differentially expressed novel psychosis- related genes was performed utilising a phencyclidine (PCP) model of schizophrenia and rat oligonucleotide GeneChips from Affymetrix. The chronic PCP model of schizophrenia has been shown to produce a pattern of metabolic hypofunction and neurochemical changes in the rodent brain that closely mirror those observed in the brains of schizophrenic patients (Cochran et al. 2003). This microarray study allowed the screening of rat genes and expressed sequence tags (ESTs) that have the potential to represent novel and uncharacterised genes. Bioinformatic analyses of the 209 significantly differentially expressed ESTs revealed 66 cDNAs. Three (Edg2, EST AI072720 and Tm4sf12) were selected as candidate genes for which to validate and characterise. Two of them, Edg2 and EST AI072720, were confirmed as differentially expressed in the rat chronic PCP model by quantitative real-time PCR. The differential expression of Tm4sf12 was not confirmed and therefore was not characterised further. Edg2 (LPA1) is a G-protein-coupled receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. Is is widely expressed but predominantly in the brain, where it was suggested to be involved in the control of myelination. Edg2 distribution in the rat brain (as revealed by in situ hybridisation) was consistent with this hypothesis. However, its increased expression in the prefrontal cortex of rats after chronic treatment with PCP, consistently with increased expression in the dorso-lateral prefrontal cortex of schizophrenic patients, suggested that Edg2 may also have a role in cortical regions which may be related to schizophrenia. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Brian Morris
Keywords: Genetics, Mental health
Date of Award: 2006
Depositing User: Enlighten Team
Unique ID: glathesis:2006-71398
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71398

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