Human cellular differences in cAMP--CREB signaling correlate with light-dependent melatonin suppression and bipolar disorder.

Authors:
Ludmila Gaspar
Ludmila Gaspar
University of Zurich
Switzerland
Anne-Sophie Johansson
Anne-Sophie Johansson
University of Zurich
Switzerland
Ermanno Moriggi
Ermanno Moriggi
Institute of Pharmacology and Toxicology
Switzerland
Bjorn Owe-Larsson
Bjorn Owe-Larsson
Skubiszewski Medical University
Poland
Gabriella B Lundkvist
Gabriella B Lundkvist
Karolinska Institutet
Sweden

Eur J Neurosci 2014 Jul 5;40(1):2206-15. Epub 2014 Jun 5.

Institute of Pharmacology and Toxicology, University of Zurich, 190 Winterthurerstrasse, Zurich, Switzerland.

Various lines of evidence suggest a mechanistic role for altered cAMP-CREB (cAMP response element - binding protein) signaling in depressive and affective disorders. However, the establishment and validation of human inter-individual differences in this and other major signaling pathways has proven difficult. Here, we describe a novel lentiviral methodology to investigate signaling variation over long periods of time directly in human primary fibroblasts. On a cellular level, this method showed surprisingly large inter-individual differences in three major signaling pathways in human subjects that nevertheless correlated with cellular measures of genome-wide transcription and drug toxicity. We next validated this method by establishing a likely role for cAMP-mediated signaling in a human neuroendocrine response to light - the light-dependent suppression of the circadian hormone melatonin - that shows wide inter-individual differences of unknown origin in vivo. Finally, we show an overall greater magnitude of cellular CREB signaling in individuals with bipolar disorder, suggesting a possible role for this signaling pathway in susceptibility to mental disease. Overall, our results suggest that genetic differences in major signaling pathways can be reliably detected with sensitive viral-based reporter profiling, and that these differences can be conserved across tissues and be predictive of physiology and disease susceptibility.

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July 2014
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References

(Supplied by CrossRef)
Antidepressant chronotherapeutics for bipolar depression
Benedetti et al.
Dialogues Clin. Neurosci. 2012
Crosstalk between the norepinephrine and serotonin systems and its role in the antidepressant response
Blier et al.
J. Psychiatr. Neurosci. 2001
Molecular insights into human daily behavior
Brown et al.
Proc. Natl. Acad. Sci. USA 2008

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