Item type:Thesis, Open Access

Verhaltensauffälligkeiten transgener Mäuse mit defizienter kooperativer DNA-Bindung des Transkriptionsfaktors STAT1

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Date

2013-06-17

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Philipps-Universität Marburg
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Abstract

Cytokines play a key role in the pathogenesis of major depressive disorder, as has been shown by the induction of depressive symptoms in interferon-α-treated patients as well as elevated serum levels of pro-inflammatory cytokines in depressed patients. In this thesis, the behavioural effects of a point mutation in the transcription factor STAT1 were investigated (signal transducer and activator of transcription 1), which resulted in a defect in cooperative DNA-binding. A substitution of a critical amino acid residue in the aminoterminal domain of STAT1 (F77A) resulted in impaired tetramer formation and defective tyrosine dephosphorylation, leading to decreased transcriptional activation of interferon-γ-responsive target genes such as mig1. In behavioural experiments using a knockin-mouse model, homozygous mice carrying the F77A missense mutation showed a depressive-like behaviour in the forced swim test without any apparent changes in locomotion and anxiety associated tests. The transgenic STAT1F77A/F77A mice showed an elevated survival rate upon intraperitoneal injection of lipopolysaccharide (LPS) and experienced impaired sickness behaviour in an early stage as compared to wild-type mice with faster recovery. Overall, the loss of cooperative DNA binding of STAT1 was associated with a depression-like behaviour and an elevated survival rate following ex- posure to LPS. These unexpected results suggest that in stark contrast to type I interfer- ons, interferon-γ initiates antidepressive effects, which are mediated by the transcription factor STAT1.

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Dates
Created: 2013Issued: 2013-06-17Updated: 2013-07-01
DOI
https://doi.org/10.17192/z2013.0323
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Interferon-Gamma STAT1 behavior depression
DFG-subjects
Interferon-Gamma STAT1 Verhalten Depression
DDC-Numbers
610
License
https://rightsstatements.org/vocab/InC-NC/1.0/
URI
https://open.uni-marburg.de/handle/10.17192/z2013.0323
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Haussmann, Jan (1038390893): Verhaltensauffälligkeiten transgener Mäuse mit defizienter kooperativer DNA-Bindung des Transkriptionsfaktors STAT1. : Philipps-Universität Marburg 2013-06-17. DOI: https://doi.org/10.17192/z2013.0323.

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