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

Ludmila Gaspar, Maan van de Werken, Anne-Sophie Johansson, Ermanno Moriggi, Bjorn Owe-Larsson, Janwillem W. H. Kocks, Gabriella B. Lundkvist, Marijke C. M. Gordijn, Steven A. Brown*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2206-2215
Number of pages10
JournalEuropean Journal of Neuroscience
Volume40
Issue number1
DOIs
Publication statusPublished - Jul-2014

Keywords

  • bipolar disorder
  • cAMP-CREB
  • circadian
  • fibroblast
  • inter-individual differences
  • melatonin
  • GENOME-WIDE ASSOCIATION
  • PLURIPOTENT STEM-CELLS
  • GENE-EXPRESSION
  • RESPONSE ELEMENT
  • CIRCADIAN CLOCKS
  • MOOD DISORDERS
  • RAT PINEALOCYTES
  • BETA-BLOCKERS
  • TRANSCRIPTION
  • PROTEIN

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