CRE -binding transcription factors mediate distinct effects of antidepressant drugs in the brain

The therapeutic efficacy of antidepressant drugs has been recognized for years, however current knowledge regarding their mechanisms of action remains incomplete. Although antidepressant drugs alter neurotransmitter concentration acutely, the symptoms of depression are alleviated only after chronic antidepressant use. This suggests that long-term molecular alterations are critical to maintain effectiveness of these drugs. cAMP response element (CRE) binding transcription factors have been implicated in antidepressant activity. To understand the roles of these transcription factors, mice containing targeted deletions of cAMP response element modulator (CREM) and cAMP response binding protein (CREB) element were examined for their behavioral, molecular and cellular responses to antidepressant treatment. In wild-type mice a repressor isoform of CREM, inducible cAMP early repressor (ICER) was upregulated in the hypothalamus following chronic antidepressant administration, suggesting a role for ICER in the endocrine response to drug treatment. Behaviorally, mice lacking ICER exhibited normal responses to antidepressant administration. However, antidepressant drugs were unable to blunt corticosterone release following swim stress in ICER mutant mice. In wild-type mice, DMI blunted induction of corticotropin releasing factor (CRF) mRNA in the hypothalamus following swim-stress, however, in ICER mutant mice, CRF mRNA levels remained elevated, suggesting that ICER is required for antidepressants to repress CRF mRNA and therefore suppression of corticosterone release. The role of related CRE-binding transcription factor, CREB, in antidepressant action was also evaluated. CREB-deficiency alone was sufficient to induce antidepressant-like behaviors in two models of antidepressant efficacy. Antidepressant treatment caused further increases in antidepressant-like behaviors in CREB mutant mice. Furthermore, swim-stress induced elevation in corticosterone was maintained in CREB-deficient mice, as was the effectiveness of antidepressants to block this response. However, increased expression of the putative CREB target gene, brain-derived neurotrophic factor, was abolished in CREB-deficient mice. Studies have also suggested a role for CREB in antidepressant-induced hippocampal neurogenesis. CREB-deficient mice demonstrated increased neurogenesis and cell survival throughout the brain; however, chronic antidepressant treatment was unable to induce further cell proliferation. Together these data reveal distinct roles for CRE-binding transcription factors in the mechanisms of action of antidepressant drugs and may provide insight into the development of novel therapeutics for clinical depression