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

Zytokine spielen in der Pathogenese der humanen Depression eine zentrale Rolle; dafür sprechen die Beobachtung depressiver Reaktionen als klinische Nebenwirkung im Zu- sammenhang mit einer Interferon-α-Therapie und die erhöhten Serumspiegel einiger inflammatorische...

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Bibliographische Detailangaben
1. Verfasser: Haussmann, Jan
Beteiligte: Meyer, Thomas (Prof. Dr. mult.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2013
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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.