CREB regulates thousands of genes, yet to date, only a handful that mediate depression or antidepressant response have been identified as relevant CREB targets.
PDE4 cyclic nucleotide phosphodiesterases regulate 3', 5' cAMP abundance in the CNS and thereby regulate PKA activity and phosphorylation of CREB, which has been implicated in learning and memory, depression and other functions.
Depression and fatigue during chronic IFN-α administration were associated with alterations in the expression (OAS2) and transcriptional control (CREB/ATF) of genes linked to behavioral disorders including CFS and major depression, further supporting an immune contribution to these diseases.
G protein-activated K+ channel 2 (GIRK2) and cAMP-response element binding protein (CREB1) are involved in synaptic plasticity and their genes have been implicated depression and memory processing.
Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF-rs6265 and CREB1-rs2253206.
The major findings were associations of TPH2 (rs12229394) with depression accompanied by fatigue in women and CREB1 (rs11904814) with depression alone in men.
Polymorphisms that span CREB1 were associated with treatment-emergent suicidality among men with depression, extending an observation of association with male anger expression in a prior independent cohort.