Molecular mechanisms of STAT1 transcription factor in the pathogenesis of depression

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Increased serum concentrations of cytokines are typically found in depressed patients, and cytokines such as interferons and interleukins have long been known to signal through transcription factors termed STAT proteins (signal transducer and activator of transcription). Given that interferons exert their intracellular effects on gene expression via activation of STAT1, this project proposal focuses on the role of STAT1 in the pathogenesis of depression-like behavior. Currently, there are no reliable data on this issue in the existing literature. Therefore, we generated a STAT1-knockin mouse line with defective cooperative DNA binding resulting in a global loss of interferon-gamma-mediated signaling and started to assess this transgenic mouse line systematically in behavioral tests. The results from these experiments demonstrated that homozygous knockin mice, when compared with their littermates expressing wild-type STAT1, exhibit a prolonged immobility in the forced-swim test. Preliminary experiments showed expression of both STAT1 and STAT3 in neurons of the hippocampal formation. In this project, we plan to study the underlying molecular mechanisms of this proposed neuroprotective effect of interferon-gamma-mediated signal transduction. Particular emphasis will be placed on the importance of heterodimerization of STAT1 and STAT3 for interferon-gamma-mediated hippocampal gene expression and its possible impact on the development of depression-like behavior.