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Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolutionsbiologi, Evolutionsbiologi. (Behavioral Genetics)
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Evolutionsbiologi. (Behavioral Genetics)
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Evolutionsbiologi. (Behavioral Genetics)
2003 (Engelska)Ingår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 54, nr 11, s. 1212-1221Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: RNA expression profiling can provide hints for the selection of candidate susceptibility genes, for formulation of hypotheses about the development of a disease, and/or for selection of candidate gene targets for novel drug development. We measured messenger RNA expression levels of 16 candidate genes in brain samples from 55 schizophrenia patients and 55 controls. This is the largest sample so far used to identify genes differentially expressed in schizophrenia brains. METHODS: We used a sensitive real-time polymerase chain reaction methodology and a novel statistical approach, including the development of a linear model of analysis of covariance type. RESULTS: We found two genes differentially expressed: monoamine oxidase B was significantly increased in schizophrenia brain (p =.001), whereas one of the serotonin receptor genes, serotonin receptor 2C, was significantly decreased (p =.001). Other genes, previously proposed to be differentially expressed in schizophrenia brain, were invariant in our analysis. CONCLUSIONS:The differential expression of serotonin receptor 2C is particularly relevant for the development of new atypical antipsychotic drugs. The strategy presented here is useful to evaluate hypothesizes for the development of the disease proposed by other investigators.

Ort, förlag, år, upplaga, sidor
2003. Vol. 54, nr 11, s. 1212-1221
Nationell ämneskategori
Fysiologi Genetik
Identifikatorer
URN: urn:nbn:se:uu:diva-90902DOI: 10.1016/S0006-3223(03)00526-2OAI: oai:DiVA.org:uu-90902DiVA, id: diva2:163419
Tillgänglig från: 2003-10-14 Skapad: 2003-10-14 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Ingår i avhandling
1. High-resolution Studies of mRNA Expression in Brain: A Search for Genes Differently Expressed in Schizophrenia
Öppna denna publikation i ny flik eller fönster >>High-resolution Studies of mRNA Expression in Brain: A Search for Genes Differently Expressed in Schizophrenia
2003 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Gene expression differences between patients and controls can be used to find susceptibility genes and drug targets for a disease. High-resolution strategies are required because the differences between the investigated groups may be small and numerous factors may affect the mRNA quantity. This thesis is based on the use of real-time RT-PCR combined with a new statistical approach, developed to detect small differences between patients and controls and differences due to patient subgroups.

Comparisons between human brain biopsy and autopsy samples showed that post-mortem tissue can be used to make conclusions on the relative mRNA levels in the living brain.

Power analysis based on human brain mRNA expression from 14 genes adjusted with two reference genes, revealed that a sample size of 50 patients and 50 controls was required to detect a 2-fold difference with a power and a confidence of 95%. A similar study in rats revealed that approximately the same sample size was required for rat brain mRNA expression studies.

The mRNA levels of several genes were studied in 55 schizophrenia and 55 control prefrontal brain autopsies, using a novel and more powerful statistical analysis. The serotonin receptor 2C gene (HTR2C) showed a significant 1.5-fold decrease in the patients as compared to controls, and the monoamine oxidase B gene (MAOB) a 1.2-fold increase.

The mechanism behind the decrease of HTR2C mRNA levels was investigated by studying the correlation of drug treatment and HTR2C promoter polymorphisms to the HTR2C expression levels. The observed decrease was present in untreated patients, suggesting that the HTR2C mRNA decrease is correlated with the disease and not the treatment. There was no association between promoter polymorphisms and HTR2C expression levels. Thus, the molecular mechanism for the decreased expression remains unclear. Nevertheless, the results support a role for monoaminergic synapses in schizophrenia.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2003. s. 47
Serie
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 894
Nyckelord
Genetics, mRNA, gene expression, real-time RT-PCR, schizophrenia, 5-HT (serotonin) receptor 2C, brain, psychiatric genetics, Genetik
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-3605 (URN)91-554-5755-X (ISBN)
Disputation
2003-11-07, Lindahlsalen, EBC, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2003-10-14 Skapad: 2003-10-14 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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