It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways—cAMP, Wnt/
Major depressive disorder (MDD) constitutes the first leading cause of years lived with disability [
The clinical phenomenology of major depression implicates brain neurotransmitter systems involved in the regulation of mood, anxiety, fear, reward processing, attention, motivation, stress responses, social interaction, and neurovegetative function [
In depressed subjects, the structures of the medial prefrontal network have been shown to contain alterations in gray matter volume, cellular elements, neurophysiological activity, receptor pharmacology, and gene expression. Dysfunction within this system underlies the disturbances in emotional behavior and other cognitive aspects of the major depressive disorder. Treatments for depression, involving pharmacological, neurosurgical, and deep brain stimulation methods, appear to suppress pathological activity within the components of medial prefrontal network such as the subgenual anterior cingulate cortex, ventromedial frontal cortex, striatum, and amygdala [
Although the causes of MDD are not yet completely known, genetic factors appear to play an important role although other factors deal with acute or chronic stress, childhood trauma, viral infections, and others [
The discovery that some drugs as iproniazid and imipramine exert an antidepressant effect dates back to the 1950s [
Traditionally, research in the neurobiology of major depressive disorder has been focused on monoamines. However, several lines of evidence [
The “neuroplasticity hypothesis” was postulated based on several findings: first, stress decrease hippocampal neurogenesis and synaptic plasticity in prefrontal cortex (PFCx) [
Dentate gyrus proliferation is decreased by stress [
It is unlikely that impaired adult hippocampal neurogenesis alone may fully explain the neuropathology of major depression. In this sense, other studies have addressed cellular proliferation in anatomical structures quite relevant to depressive disorders, such as prefrontal cortex and amygdala, by using animal models of depression. Thus, medial frontal cortex presents a reduction in cell proliferation [
The disturbed adult hippocampal neurogenesis cannot fully explain major depression. It could only be the most conspicuous feature of a more fundamental type of cellular plasticity, which could also govern the prefrontal cortex and other regions. It has also been proposed that, in addition to neural proliferation, changes in synaptic plasticity would also be involved in the biological basis of depression [
An increased apoptosis has also been related to a higher risk of suffering major depression since increased cell death in areas as dentate gyrus (DG), CA1, and CA4 areas of the hippocampus, entorhinal cortex, and subiculum are reported in studies using human postmortem brain samples though this phenomenon does not seem to account for the hippocampal volume reduction [
It has been suggested that an increase in serotonin levels mediates the raise in cell proliferation, while the depletion of this neurotransmitter does not lead to an immediate effect over the hippocampal cell division [
RS67333 increases the number of ANPs (b) and neuroblasts type 1 (c) that express
Classically, the modulation of different neurotransmitter systems has been implicated in the mediation of the antidepressant effects, and, for some of them, a link with proliferative or plastic changes has been reported. The traditionally involved neurotransmitter systems include the serotonergic, adrenergic, and dopaminergic ones, while others, such as the glutamatergic and cannabinoid systems and the corticotropin-releasing factor (CRF) system implicated in the secretion of ACTH are acquiring increasing importance in the last years. Here we will focus on the serotonergic receptors most relevant to modulating neural proliferation and synaptic plasticity processes.
Serotonin has a positive role in the regulation of hippocampal neurogenesis. The partial lesion of dorsal and medial raphe nuclei, which results in a decrease of serotonergic neurons that innervate the dentate gyrus of the hippocampus and other projection areas as cortex and amygdala, decreases the proliferation in the subgranular zone of the dentate gyrus [
The importance of this serotonergic subtype in the effects of antidepressants has been shown in studies in vivo using 3 day treatment with the
Role of the activation and blockade of the different serotonin receptor subtypes in neural proliferation and synaptic plasticity.
Serotonin receptor subtypes | Effect of pharmacological manipulation on hippocampal proliferation | ko | ||||
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= proliferation |
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blocks 5-HT-induced proliferation | [ |
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5-HT2A/2C | = proliferation (+SSRI) |
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↑ plasticity markers and BDNF (+SSRI, subchronic) | [ |
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5-HT4 |
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Blocks 5-HT-induced proliferation |
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5-HT6 |
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5-HT7 |
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= proliferation | [ |
The role of the
In the last years, the 5-HT4 receptor subtype has been proven to have an outstanding role on the depressive pathology. This receptor subtype density and signaling cascade through cAMP are up-regulated in the frontal cortex and caudate-putamen of depressed humans [
The role of the 5-HT6 receptor subtype in depression is not clear, but tricyclic antidepressants as amitriptyline and atypical antidepressants as mianserin have high affinity for this serotonin receptor subtype, acting as antagonists [
The 5-HT7 receptor subtype is also involved in the antidepressant effect. Recent studies have shown that the blockade of the 5-HT7 receptor subtype produces antidepressant-like behaviour [
In an attempt to explain those brain changes implicated on depression and/or antidepressant effect that could not be included in the initial monoaminergic hypothesis of depression, it was postulated the so-called “Neurotrophic hypothesis of Depression” that later was revised to a “new” “hypothesis of neuroplasticity” [
The infusion of BDNF in brain [
Chronic administration of antidepressants produces an increase in hippocampal BDNF mRNA expression and BDNF protein levels (Figure
BDNF mRNA expression (a) and protein level (b) in the dentate gyrus of the hippocampus (DG) or total hippocampus, respectively, after 7-day treatment with the 5-HT4 partial agonist RS67333 (1.5 mg/kg/day) (modified from [
The main role of BDNF regarding adult neurogenesis is not linked to proliferation, but to the increase in cell survival, as described using BDNF and its receptor TrkB knock-out animals which present a reduced BDNF expression [
The existence of a single-nucleotide polymorphism (SNP) in the human BDNF gene, BDNF (Val66Met) is associated to reduced BDNF secretion [
Other important trophic factor is the vascular endothelial growth factor (VEGF) implicated in the “vascular niche hypothesis of adult neurogenesis.” This theory proposes the need of vascular recruitment associated to active sites of neurogenesis formed by proliferative cells that present an endothelial phenotype in 37% of the cases [
Some antidepressant treatments, as the electroconvulsive therapy (ECS) [
Even though these data indicate the importance of VEGF brain levels in the depressive disorder, preliminary reports do not show a clear correlation between peripheral VEGF and depressive disorders, not allowing for the use of this molecule as a marker of depression and/or antidepressant response [
The activation of receptor tyrosine kinases by neurotrophic factors promotes the activation of the PI3K/Akt pathway that is linked to the Wnt/
The upstream and downstream components of the cAMP signaling pathway have been extensively involved in the pathophysiology of mood disorders as well as in the actions of antidepressant drugs. Alterations in several elements of this pathway, such as G proteins (Gs or Gi), adenylate cyclase (AC), cAMP levels, cAMP-dependent protein kinase (PKA), and the cAMP response element-binding protein (CREB) transcription factor, have been described in peripheral cells and the postmortem brain of patients with affective disorders, both untreated or after antidepressant therapy [
Involvement of cAMP, Wnt/
Signaling pathways | Changes related to disease or treatment | Direct effect | |||||||
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Nontreated MDD (versus control) | Treated MDD (versus untreated) | ||||||||
Change | Region | Reference | Change | Region | Reference | Change | Reference | ||
cAMP/PKA | cAMP |
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Human PFCx | [ |
cAMP (administration/degradation inhibition) |
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↑ AC CB1-induced inhibition | [ |
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PKA |
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↑ PKA activity | [ |
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CREB |
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↑ CREB (protein, expression, activity) | Hp, Cx |
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CREB viral expression in Hp |
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CREB viral expression in Acb |
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Epac |
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Hp, PFCx | [ |
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Wnt/ |
GSK- |
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Hp | [ |
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Hp | [ |
GSK-3 |
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GSK-3 |
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GSK-3 |
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PFCx |
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mTOR | mTOR |
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PFCx | [ |
Activation (NMDAr antagonists) |
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In peripheral cells and postmortem brains of patient with mayor depression, there is a reduction of the adenylyl cyclase (AC) activity in response to forskolin [
Antidepressant treatment increases basal cAMP in both rat and human. (a) Increase of basal cAMP levels in rat hippocampus, frontal cortex and striatum after chronic (14 days) antidepressant treatment with fluoxetine (10 mg/kg/day) and venlafaxine (40 mg/kg/day), and subchronic treatment (3 days) with the 5HT4 agonist RS67333 (1.5 mg/kg/day) and in postmortem frontal cortex samples from control, antidepressant free-depressed subjects (AD-free MD) and antidepressant-treated depressed subjects (AD-treated MD). cAMP is expressed in pmoles/mg protein. *
The next step in this signaling pathway is the activation of cAMP-dependent protein kinase (PKA) by cAMP, so that PKA activity is increased after chronic antidepressant administration [
CREB has been widely involved in the pathophysiology of depression and both behavioural and cellular responses to antidepressant treatments [
Western blot analyses of hippocampal CREB (a) and p-CREB (b) levels and ratio p-CREB/CREB (c) after chronic antidepressant treatment (14 days) with fluoxetine (10 mg/kg/day) and venlafaxine (40 mg/kg/day). Note that p-CREB levels and ratio p-CREB/CREB are increased after fluoxetine treatment, but not total CREB, or after venlafaxine treatment in total cell lysate from hippocampus of rats. Values are means ± S.E.M. Corresponding to densitometry levels of the proteins expressed as the percentage of the same proteins in vehicle-treated animals. *
A growing body of data shows that other signalling cascades can modulate CREB activity through phosphorylation, such as the calcium/calmodulin-dependent kinase (CaMKII) and the mitogen-activated protein (MAP) kinase cascades, and may also be implicated in the mechanism of action of antidepressants [
Initially, all effects of cAMP increase were attributed to the activation of PKA/CREB, but two novel targets as the cAMP-regulated ion channels and Epac (exchange protein directly activated by cAMP) are now known to be involved in mediating cAMP responses. An increase in Epac-2 levels, but not Epac-1, has been found in postmortem samples of prefrontal cortex and hippocampus of depressed subjects [
The Wingless-type (Wnt) family of proteins has key roles in many fundamental processes during neurodevelopment [
In the absence of Wnt signaling,
In the last years several evidences have implicated Wnt-signaling pathway in the pathophysiology and treatment of mood disorders and other cognitive pathologies. GSK-3
Postmortem human brain samples from depressed subjects and teenage suicide victims present a dysregulation of Wnt/GSK-3
The inhibition of GSK-3
Recent studies have identified the Wnt/GSK-3
Wnt/
Implication on
Other treatments with antidepressant-like efficacy, such as the subchronic administration of SSRI fluoxetine together with the
In addition, Frizzled receptors and GPCRs can interact through several pathways [
Target of rapamycin (TOR) genes, members of the phosphoinositol kinase-related kinase (PIKK) family of kinases [
In neurons, mTORC1 activity is regulated by phosphorylation in response to growth factors, as BDNF, mitogens, hormones, and neurotransmitters through the activation of G protein-coupled receptors (GPCRS) or ionotropic receptors. The mTORC1 phosphorylation is mediated by ERK/MAPK, PI3K, PKA, and Epac. The activation of mTORC1 results in the phosphorylation and activation of several downstream targets as the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), p70 ribosomal S6 kinase (p70S6K), RNA helicase cofactor eIF4A, extracellular signal-regulated kinase (ERK, including both ERK1 and ERK2), or PKB/Akt; and the inhibition of the eukaryotic elongation factor 2 kinase (eEF2) [
mTOR has been extensively studied related to cancer, development, metabolism, and more recently to the central nervous system (CNS) physiology and diseases [
mTOR-signaling pathway has been also related to a number of neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, tuberous sclerosis, neurofibromatosis, fragile X syndrome, epilepsy, brain injury, and ischemic stroke [
Recent studies have also associated mTOR signaling in affective disorders since the administration of ketamine produces a fast-acting antidepressant-like effect in animals [
The subchronic, but not acute, administration of rapamycin in rodents has an antidepressant-like effect shown in two behavioural tests as forced swimming and tail suspension tests [
The neurogenesis hypothesis of depression was based upon the demonstration that stress decreased adult neurogenesis in the hippocampus. This reduction in the production of newborn granule cells in the hippocampal dentate gyrus is related to the pathophysiology of depression. Since then, several studies have established that newborn neurons in the dentate gyrus are required for mediating some of the beneficial effects of antidepressant treatments since the increase in cell proliferation after antidepressant treatment is only observed in the SGZ and not in SVZ, suggesting a specificity of the antidepressants to regulate hippocampal neurogenesis. Moreover, psychotropic drugs without antidepressant activity do not increase neurogenesis [
The appearance of the antidepressant-like effect in behavioural tests after 2-3 weeks parallels the time needed for the growth of newborn cells in hippocampus [
The putative role of changes in synaptic plasticity and/or neural proliferation in the depressive pathology is proposed some time ago [
The rapid antidepressant response to drugs as ketamine acting through the blockade of NMDA receptors appears as a new target for having fast-acting effects on the treatment of mood disorders compared to the weeks or months required for standard medications. Ketamine and other glutamate antagonists through the increase of the number and function of new spine synapses in rat prefrontal cortex by the activation of mTOR [
It would also be critical for future work to validate the relative importance of antidepressant-induced neurogenesis and synaptic plasticity in the antidepressant effects. However, evidence is strong that neurogenesis is required for at least some of the beneficial effects of antidepressant treatment. The exact role of neuroplastic/neuroproliferative changes in other brain structures as mPFCx and amygdala should be elucidated.
As indicated in this review, the importance of either proliferation or plasticity, or both, is still a matter of debate. As the involvement of proliferation and plasticity has been mainly studied in hippocampus, we might be underestimating its role in the antidepressant effect. In this sense, as the hippocampus is responsible for the learning and cognition part of the depressive disorder, the fact that the impairment of hippocampal proliferation would not block the antidepressant effect of some drugs does not necessarily conclude that the proliferation is only dependent on hippocampus. In the last years, prefrontal cortex, a structure with a great importance in mood control and working memory, is gaining increasing relevance in the plastic changes linked to antidepressant effects promoted by drugs as ketamine. In this sense, hippocampal proliferation would be only a small part of the plastic changes that are taking place within the hippocampus, and other brain areas. Thus, we must not underestimate the implication of synaptic plasticity in those antidepressant treatments that are not accompanied with increased proliferation.
The authors wish to thank Rebeca Madureira, Alicia Martín, Beatriz Romero, Isabel Ruiz, María Josefa Castillo, and Lourdes Lanza for their technical assistance. The scientific work of former coworkers Olga Guitérrez, Susana Mato, Elena del Olmo, Antonio Rodríguez-Gaztelumendi, and María Luisa Rojo is kindly acknowledged. This research was supported by Ministry of Science, SAF04-00941, SAF07-61862, Fundación Alicia Koplowitz, Fundación de Investigación Médica Mutua Madrileña, Instituto de Salud Carlos III, and University of Cantabria-FAES research contract. Rebecca Vidal has been the recipient of a fellowship from University of Cantabria-FAES, and a CIBERSAM contract.