The Role of CREB in Depression and Antidepressant Treatment

doi:10.1016/j.biopsych.2005.11.003

Biological Psychiatry

Volume 59, Issue 12, 15 June 2006, Pages 1144-1150

https://doi.org/10.1016/j.biopsych.2005.11.003 Get rights and content

Major depressive disorder is a severe clinical problem across the globe, with a lifetime risk of 10%–30% for women and 7%–15% for men. The World Health Organization ranks major depression at the top of the list in terms of disease burden, and this burden is expected to rise in the next decade as the prevalence of the disorder grows. Since the late 1950s, a wide range of antidepressant medications targeting the monoamine systems has been available to alleviate the symptoms of major depressive disorder. Although widely prescribed, such antidepressant medications are accompanied by a delay in effectiveness, as well as varied side effects. Therefore, further characterization of the biological mechanisms behind their function is crucial for the development of new and more effective treatments. One protein that could serve as a convergence point for multiple classes of antidepressant drugs is the transcription factor CREB (cyclic adenosine monophosphate response element binding protein). CREB is upregulated by chronic antidepressant treatment, and increasing CREB levels in rodent models results in antidepressant-like behaviors. Furthermore, postmortem studies indicate that CREB levels are increased in subjects taking antidepressants at the time of death. However, not all antidepressants increase CREB levels and/or activity, and reducing CREB levels in some brain regions also results in antidepressant-like behaviors. This review attempts to consolidate the information relevant to the structure and function of the CREB protein and describe how this relates to the mechanism of antidepressant drugs. Animal models in which CREB function is enhanced, by overexpression of the protein, or reduced, by expression of mutant forms of the protein or through gene deletion experiments, are summarized in terms of identifying a role for CREB in behavioral responses in depression tests that were originally designed to evaluate antidepressant efficacy. Human postmortem and genetic studies that implicate CREB in depression and antidepressant efficacy are also discussed.

Section snippets

Identification of CREB

Early studies aimed at understanding the molecular mechanism associated with cAMP-dependent induction of genes identified an 8-base-pair cAMP-responsive element (CRE; 5′TGACGTCA-3′) that is required for initiation of somatostatin gene transcription (Montminy et al 1986). With affinity chromatography, the CRE was shown to bind a protein in pheochromocytoma cell nuclear extracts, from which CREB protein was later purified (Montminy and Bilezikjian 1987). Subsequently, human, rat, and mouse

Alterations in CREB After Antidepressant Drug Administration

Antidepressant drugs facilitate signaling of 5HT or NE, either by inhibiting reuptake to presynaptic terminals, inhibiting catabolism, binding to serotonin or noradrenergic receptors, or a combination of effects. All these events take place soon after drug administration, however, clinical antidepressant effects develop slowly in the weeks after continuous drug treatments (Nestler et al 2002). The majority of studies examining alterations in CREB after chronic antidepressant drug administration

Behavioral Responses to Antidepressant Drugs in CREB Animal Models

Depression is a disease manifested primarily at the psychological and behavioral level, which has made it difficult to mimic in animal models; however, despite these difficulties, various paradigms have been developed to investigate prodepressant-like or antidepressant-like behaviors in mice and rats (Cryan and Mombereau 2004).

Several rodent models have been developed to study the specific role of CREB in these behavioral paradigms through the generation of knockout mice or viral overexpression

Postmortem Studies

Results from animal studies suggest that activation of CREB is associated with antidepressant efficacy; however, clinical postmortem studies provide the strongest support for this hypothesis. Patients taking an antidepressant at the time of death showed an increased level of CREB (Dowlatshahi et al 1998), whereas those who were not medicated at the time of death showed decreased levels of CREB in temporal cortex. Reductions of CREB and phosphorylated CREB were also found in the orbitofrontal

Conclusion

Identification of molecular mechanisms underlying antidepressant treatment might help to determine genetic variations that give rise to depression. The transcription factor CREB seems to be involved in both the mechanism of action of antidepressants as well as the disease itself, though these genetic linkage studies are limited to a small subset of depressed individuals. The signs of depression include depressed mood, diminished interest or pleasure in activities, feelings of worthlessness, and

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Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is linked to the pathophysiology of depression. Although exogenous adrenocorticotropic hormone (ACTH) is associated with a depressive-like phenotype in rodents, comprehensive neurobehavioral and mechanistic evidence to support these findings are limited. Sprague-Dawley rats (male, n = 30; female, n = 10) were randomly assigned to the control (male, n = 10) or ACTH (male, n = 20; female n = 10) groups that received saline (0.1 ml, sc.) or ACTH (100 μg/day, sc.), respectively, for two weeks. Thereafter, rats in the ACTH group were subdivided to receive ACTH plus saline (ACTH_S; male, n = 10; female, n = 5; 0.2 ml, ip.) or ACTH plus imipramine (ACTH_I; male, n = 10; female, n = 5;10 mg/kg, ip.) for a further four weeks. Neurobehavioral changes were assessed using the forced swim test (FST), the sucrose preference test (SPT), and the open field test (OFT). Following termination, the brain regional mRNA expression of BDNF and CREB was determined using RT-PCR. After two-weeks, ACTH administration significantly increased immobility in the FST (p = 0.03), decreased interaction with the center of the OFT (p < 0.01), and increased sucrose consumption (p = 0.03) in male, but not female rats. ACTH administration significantly increased the expression of BDNF in the hippocampus and CREB in all brain regions in males (p < 0.05), but not in female rats. Imipramine treatment did not ameliorate these ACTH-induced neurobehavioral or molecular changes. In conclusion, ACTH administration resulted in a sex-specific onset of depressive-like symptoms and changes in brain regional expression of neurotrophic factors. These results suggest sex-specific mechanisms underlying the development of depressive-like behavior in a model of ACTH-induced HPA axis dysregulation.
Transcriptomic analyses of rats exposed to chronic mild stress: Modulation by chronic treatment with the antipsychotic drug lurasidone
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Exposure to stressful experiences accounts for almost half of the risk for mental disorders. Hence, stress-induced alterations represent a key target for pharmacological interventions aimed at restoring brain function in affected individuals. We have previously demonstrated that lurasidone, a multi-receptor antipsychotic drug approved for the treatment of schizophrenia and bipolar depression, can normalize the functional and molecular impairments induced by stress exposure, representing a valuable tool for the treatment of stress-induced mental illnesses. However, the mechanisms that may contribute to the therapeutic effects of lurasidone are still poorly understood. Here, we performed a transcriptomic analysis on the prefrontal cortex (PFC) of adult male rats exposed to the chronic mild stress (CMS) paradigm and we investigated the impact of chronic lurasidone treatment on such changes. We found that CMS exposure leads to an anhedonic phenotype associated with a down-regulation of different pathways associated to neuronal guidance and synaptic plasticity within the PFC. Interestingly, a significant part of these alterations (around 25%) were counteracted by lurasidone treatment. In summary, we provided new insights on the transcriptional changes relevant for the therapeutic intervention with lurasidone, which may ultimately promote resilience.
Differential targeting of lysophosphatidic acid LPA<inf>1</inf>, LPA<inf>2</inf>, and LPA<inf>3</inf> receptor signalling by tricyclic and tetracyclic antidepressants.
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We previously reported that in different cell types antidepressant drugs activate lysophosphatidic acid (LPA) LPA₁ receptor to induce proliferative and prosurvival responses. Here, we further characterize this unique action of antidepressants by examining their effects on two additional LPA receptor family members, LPA₂ and LPA₃. Human LPA_1-3 receptors were stably expressed in HEK-293 cells (HEK-LPA₁, -LPA₂ and –LPA₃ cells) and their functional activity was determined by Western blot and immunofluorescence. LPA effectively stimulated the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in HEK-LPA₁, -LPA₂, and -LPA₃ cells. The tricyclic antidepressants amitriptyline, clomipramine, imipramine and desipramine increased phospho-ERK1/2 levels in HEK-LPA₁ and –LPA₃ cells but were relatively poor agonists in LPA₂-expressing cells. The tetracyclic antidepressants mianserin and mirtazapine were active at all three LPA receptors. When combined with LPA, both amitriptyline and mianserin potentiated G_i/o-mediated phosphorylation of ERK1/2 induced by LPA in HEK-LPA₁, -LPA₂ and -LPA₃ cells, CHO–K1 fibroblasts and HT22 hippocampal neuroblasts. This potentiation was associated with enhanced phosphorylation of CREB and S6 ribosomal protein, two molecular targets of activated ERK1/2. The antidepressants also potentiated LPA-induced G_q/11-mediated phosphorylation of AMP-activated protein kinase in HEK-LPA₁ and –LPA₃ cells. Conversely, amitriptyline and mianserin were found to inhibit LPA-induced Rho activation in HEK-LPA₁ and LPA₂ cells. These results indicate that tricyclic and tetracyclic antidepressants can act on LPA₁, LPA₂ and LPA₃ receptor subtypes and exert differential effects on LPA signalling through these receptors.
Mitochondrial dysfunction: A fatal blow in depression
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Mitochondria maintain the normal physiological function of nerve cells by producing sufficient cellular energy and performing crucial roles in maintaining the metabolic balance through intracellular Ca²⁺ homeostasis, oxidative stress, and axonal development. Depression is a prevalent psychiatric disorder with an unclear pathophysiology. Damage to the hippocampal neurons is a key component of the plasticity regulation of synapses and plays a critical role in the mechanism of depression. There is evidence suggesting that mitochondrial dysfunction is associated with synaptic impairment. The maintenance of mitochondrial homeostasis includes quantitative maintenance and quality control of mitochondria. Mitochondrial biogenesis produces new and healthy mitochondria, and mitochondrial dynamics cooperates with mitophagy to remove damaged mitochondria. These processes maintain mitochondrial population stability and exert neuroprotective effects against early depression. In contrast, mitochondrial dysfunction is observed in various brain regions of patients with major depressive disorders. The accumulation of defective mitochondria accelerates cellular nerve dysfunction. In addition, impaired mitochondria aggravate alterations in the brain microenvironment, promoting neuroinflammation and energy depletion, thereby exacerbating the development of depression. This review summarizes the influence of mitochondrial dysfunction and the underlying molecular pathways on the pathogenesis of depression. Additionally, we discuss the maintenance of mitochondrial homeostasis as a potential therapeutic strategy for depression.
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Dopamine and serotonin signalling are associated with major depressive disorder, which is a prevalent life-threatening illness worldwide. Numerous FDA-approved dopamine/serotonin signalling-modifying drugs are available but are associated with concurrent side effects and limited efficacy. Thus, identifying and targeting their signalling pathway is crucial for improving depression treatment. Here, we determined that serotonin receptor 2A (5-HT2AR) abundantly forms a protein complex with dopamine receptor 1 (D1R) in high abundance via its carboxy-terminus in the brains of mice subjected to various chronic stress paradigms. Furthermore, the D1R/5-HT2AR interaction elicited CREB/ERK/AKT modulation during synaptic regulation. An interfering peptide (TAT-5-HT2AR-SV) agitated the D1R/5-HT2AR interaction and attenuated depressive symptoms accompanied by CREB/ERK molecule costimulation. Interestingly, HDAC antagonism but not TrkB antagonism reversed the antidepressant effect of competitive peptides. These findings revealed a novel D1R/5-HT2AR heteroreceptor complex mechanism in the pathophysiology of depression, and their uncoupling ameliorates depressive-like behaviours through HDAC-, and not BDNF-, dependent mechanisms.
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Investigating the effect of saffron carotenoids, Crocin and Crocetin, on depression and anxiety in rats by emphasizing some signaling pathways involved.
Depression and anxiety were induced in rats via unpredictable chronic mild stress (UCMS). Then different rat groups were treated with Crocin, Crocetin, Fluoxetine, and vehicle. Behavioral tests were done before and after treatment.
The serum Serotonin and Corticosterone and the expression of some hippocampal signaling proteins were studied. Furthermore, bioinformatics tools were used to predict the interactions of Crocin/ Crocetin with the Serotonin transporter and NMDA receptor subunit NR2B. Then, the patch-clamp was used to study the interaction of Crocetin with the NMDA receptor.
Various behavioral tests confirmed the induction of depression and the improvement of depression by these natural carotenoids. In addition, Crocin/ Crocetin significantly increased the decreased serum Serotonin and reduced the increased serum Corticosterone in the depressed groups. They also increased or caused a trend of increase in the CREB, ERK, BAD, BDNF, p11, and 5-HT1B expression in the hippocampus of the depressed groups. In addition, there were an increase or a trend in p-CREB/CREB, p-ERK_1/2 /ERK_1/2, and p-BAD/BAD ratios in the Crocin/ Crocetin treated depressed groups. However, the NR2B and FOXO3a expression showed a trend of decrease in depressed groups after treatment. The bioinformatics data indicated that Crocin/ Crocetin could bind to the Serotonin transporter (SLC6A4) and NR2B subunit of the NMDA receptor. Both carotenoids bind to the same site as Fluoxetine in the SLC6A4. However, they bound to different sites on the NR2B. So, Crocetin binds to NR2B at the same site as Ifenprodil. But Crocin bound to another site. The whole cell patch-clamp recording on the normal rat hippocampus revealed a significant decrease in the NMDA peak amplitude after Crocetin treatment, indicating its inhibitory effect on this receptor.
The antidepressant activities of Crocin/ Crocetin are possibly due to their effects on Serotonin and Corticosterone serum concentrations, NR2B expression, and the downstream signaling pathways. Furthermore, these natural carotenoids, like Fluoxetine, induced an increasing tendency in p11 and 5HT1B in depressed rats.

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ReviewThe Role of CREB in Depression and Antidepressant Treatment

Section snippets

Identification of CREB

Alterations in CREB After Antidepressant Drug Administration

Behavioral Responses to Antidepressant Drugs in CREB Animal Models

Postmortem Studies

Conclusion

Neuropsychopharmacology

Trends Neurosci

Biol Psychiatry

Genomics

Mol Cell

Cell

Prog Neuropsychopharmacol Biol Psychiatry

J Biol Chem

J Biol Chem

Cell

Eur J Pharmacol

Curr Biol

J Psychiatr Res

Neuron

Neurobiol Dis

Neuron

Am J Prev Med

Neuron

Cell

Lancet

Biol Psychiatry

Neuron

Eur J Pharmacol

Cell

Neuron

Behav Neural Biol

Neuron

J Biol Chem

Biol Psychiatry

Two distinct forms of active transcription factor CREB (cAMP response element binding protein)

Proc Natl Acad Sci U S A

Activating transcription factor 1 and CREB are important for cell survival during early mouse development

Mol Cell Biol

Targeting of the CREB gene leads to up-regulation of a novel CREB mRNA isoform

EMBO J

A non-selective cation current activated via the multifunctional Ca(2+)-calmodulin-dependent protein kinase in human epithelial cells

J Physiol

Phosphorylated CREB binds specifically to the nuclear protein CBP

Nature

cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs

J Neurosci

The impact of treatment-resistant depression on health care utilization and costs

J Clin Psychiatry

In search of a depressed mouseUtility of models for studying depression-related behavior in genetically modified mice

Mol Psychiatry

Alternative usage of initiation codons in mRNA encoding the cAMP-responsive-element modulator generates regulators with opposite functions

Proc Natl Acad Sci U S A

Increased temporal cortex CREB concentrations and antidepressant treatment in major depression

Lancet

Review
The Role of CREB in Depression and Antidepressant Treatment