Antidepressant action: The roles of brain-derived neurotrophic factor, Wnt signaling, and cyclic AMP response element binding

Open Access
Author:
Klabonski, Lauren Allison
Area of Honors:
Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Bernhard Luscher, Thesis Supervisor
  • Bernhard Luscher, Honors Advisor
  • Stephen Wade Schaeffer, Faculty Reader
Keywords:
  • antidepressant
  • BDNF
  • Wnt
  • CREB
Abstract:
Major depressive disorder (MDD) is a debilitating mood disorder with significant lifetime risk and high social costs. In the United States, the lifetime prevalence of MDD is almost 17%. Antidepressants are effective in treating symptoms of MDD, but the precise mechanisms by which they work are still largely unknown. The neurotrophin brain-derived neurotrophic factor (BDNF) is of special interest as it is required the therapeutic action of antidepressant drugs. BDNF itself exhibits antidepressant-like activity in animal models of MDD. Chronic antidepressant treatment increases total BDNF expression levels in the hippocampus and frontal cortex. Transcriptional regulation of the BDNF gene is extremely complex. Alternative splicing of human BDNF transcripts can theoretically result over thirty unique mRNAs. Chronic treatment with the antidepressants fluoxetine (SSRI), duloxetine (NRI), and desipramine (TCA) results in increased relative expression of BDNF transcripts in the hippocampus. Duloxetine and desipramine increase relative expression of BDNF transcripts in the frontal cortex as well. BDNF Exon IV expression increases in both the hippocampus and frontal cortex after chronic treatment with the largest variety of antidepressants. Exon IV is hypothesized to be highly targeted by the mechanisms of antidepressant function. Inhibiting cyclic AMP response element binding protein (CREB) binding prevents expression of BDNF Exon IV. Enhanced CREB binding from chronic treatment with antidepressants is likely involved in the relative increase in BDNF Exon IV expression. Chronic antidepressant administration activates canonical Wnt signaling. Additionally, overexpression of Wnt genes reduces depressive-like behaviors. There is a significant interaction in retinal cells where Wnt signaling activates BDNF expression. Wnt signaling also increases activity of calcium/calmodulin-dependent kinase IV (CaMK-IV) activity and levels of phosphorylated CREB (pCREB). This review proposes a mechanism for the increase in BDNF expression in response to chronic antidepressant treatment. Chronic antidepressant treatment activates the canonical Wnt pathway. Wnt signaling increases CaMK-IV activity, and increased CaMK-IV activity results in increased pCREB. CREB acts as a sequence-specific DNA binding protein and, in its phosphorylated form, activates transcription of target genes linked to CREB binding sites. CREB binding activates transcription, and BDNF expression increases. This mechanism is most thoroughly supported by observed effects of the TCA desipramine on these components. A connection needs to be established between chronic desipramine treatment and activation of Wnt signaling before this mechanism can be further explored and validated.