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Review Article

Signaling Pathways Regulating Gene Expression, Neuroplasticity, and Neurotrophic Mechanisms in the Action of Antidepressants: A Critical Overview

Center of Neuropharmacology, Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milan, Italy (D.T., E.T., L.M., G.R., M.P.); and Biological Psychiatry Unit, Istituto di Ricovero e Cura a Carattere Scientifico Centro S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy (J.P., G.R.)

Abstract

I. Introduction: Regulation of Gene Expression and Neuroplasticity

II. The Action of Antidepressants on cAMP-Responsive Element Binding Protein Expression and Function: Overview of Present Evidence and Hypotheses

A. The cAMP-Protein Kinase A Cascade in the Action of Antidepressants: Available Evidence

1. Nuclear Protein Kinase A.

2. Protein Kinase A in Microtubules.

3. G Protein-Adenylyl Cyclase Coupling.

4. Protein Kinase A and Dopamine- and cAMP-Regulated Phosphoprotein of Mr 32,000.

III. Signaling Pathways and Protein Kinases Regulating cAMP-Responsive Element Binding Protein Phosphorylation and Function

A. Neurotransmitter and Hormone Signaling to cAMP-Responsive Element Binding Protein

B. Synaptic Activity and Calcium Signaling to cAMP-Responsive Element Binding Protein

C. Growth Factor- and Stress-Induced Signaling to cAMP-Responsive Element Binding Protein

IV. The Complexity of cAMP-Responsive Element Binding Protein-Regulating Signaling and the Action of Antidepressants

V. cAMP-Responsive Element Binding Protein Target Genes: The Example of Brain-Derived Neurotrophic Factor

A. Evidence of Antidepressant Action on Brain-Derived Neurotrophic Factor

B. Regulation of Brain-Derived Neurotrophic Factor Expression: An Additional Layer of Complexity

VI. Conclusions

Regulation of gene expression represents a major component in antidepressant drug action. The effect of antidepressant treatments on the function of cAMP-responsive element binding protein (CREB), a transcription factor that regulates expression of several genes involved in neuroplasticity, cell survival, and cognition, has been extensively studied. Although there is general agreement that chronic antidepressants stimulate CREB function, conflicting results suggest that different effects may depend on drug type, drug dosage, and different experimental paradigms. CREB function is activated by a vast array of physiological stimuli, conveyed through a number of signaling pathways acting in concert, but thus far the effects of antidepressants on CREB have been analyzed mostly with regard to the cAMP-protein kinase A pathway. A growing body of data shows that other major pathways, such as the calcium/calmodulin-dependent kinase and the mitogen-activated kinase cascades, are involved in activity-dependent regulation of gene expression and may also be implicated in the mechanism of action of antidepressants. In this article the available evidence is reviewed with an attempt to identify the reasons for experimental discrepancies and possible directions for future research. Particularemphasis is given to the regulation of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene, which has been implicated in both the pathophysiology and pharmacology of mood disorders. The array of different results obtained by various groups is analyzed with an eye on recent advancements in the regulation of BDNF transcription, in an attempt to understand better the mechanisms of drug action and dissect molecular requirements for faster and more efficient antidepressant treatment.

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