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Forkhead Box O Transcription Factors as Possible Mediators in the Development ofMajor Depression
Haitao Wang, Rémi Quirion, Peter J. Little, Yufang Cheng, Zhong-Ping Feng, Hong-Shuo Sun, Prof. Jiangping Xu, Ph.D, MD., Prof. Wenhua Zheng, MD, PhD.
PII: S0028-3908(15)30066-6
DOI: 10.1016/j.neuropharm.2015.08.020
Reference: NP 5966
To appear in: Neuropharmacology
Received Date: 11 March 2015
Revised Date: 22 July 2015
Accepted Date: 12 August 2015
Please cite this article as: Wang, H., Quirion, R., Little, P.J., Cheng, Y., Feng, Z.-P., Sun, H.-S., Xu, J.,Zheng, W., Forkhead Box O Transcription Factors as Possible Mediators in the Development of MajorDepression, Neuropharmacology (2015), doi: 10.1016/j.neuropharm.2015.08.020.
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Forkhead Box O Transcription Factors as Possible Mediators in
the Development of Major Depression
Haitao Wang1,2, Rémi Quirion3, Peter J. Little4, Yufang Cheng1, Zhong-Ping Feng5,
Hong-Shuo Sun5, Jiangping Xu1,*, Wenhua Zheng2,*
1Guangdong Provincial Key Laboratory of New Drug Screening, School of
Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China;
2 Faculty of Health Sciences, University of Macau, Taipa, Macau, China and Key
Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University,
Guangzhou 510006, China.
3Douglas Mental Health University Institute, McGill University, Montreal, Canada;
4 School of Pharmacy, The University of Queensland, QLD 4072, Australia;
5 Department of Physiology, Faculty of Medicine, University of Toronto, Toronto,
Ontario, Canada.
*Corresponding author Prof. Jiangping Xu, Ph.D, MD. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China. Tel:/Fax:+86 20 6164 8236, E-mail address: [email protected] Prof. Wenhua Zheng, MD, PhD. Faculty of Health Sciences, University of Macau Room 4021, Building E12, Avenida de Universidade, Taipa, Macau. China Tel: +853-88224919; Email: [email protected]
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Abstract
Forkhead box O (FoxO) transcription factors play important roles in cellular
physiology and biology. Recent findings indicate that FoxOs are also involved in the
development of major depressive disorder. Alterations in the upstream molecules of
FoxOs, such as brain derived neurotrophic factor or protein kinase B, have been
linked to depression. Antidepressants, such as imipramine and venlafaxine, modify
the FoxOs phosphorylation. Furthermore, FoxOs could be regulated by serotonin and
norepinephrine receptor signaling as well as the hypothalamic-pituitary-adrenal axis,
all of which are involved in the pathogenesis of depression. FoxOs also regulate
neuronal morphology, synaptogenesis and adult hippocampal neurogenesis, which are
viewed as candidate mechanisms for the etiology of depression. In this review, we
emphasize the possible roles of FoxOs during the development of depression and
make some strategic recommendations for future research. We propose that FoxOs
and its signaling pathways may constitute potential therapeutic targets in the treatment
of depression.
Keywords: FoxO, major depression, PI3K/Akt, neuronal atrophy, neurogenesis,
antidepressants
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1. Introduction
Major depression is one of the most severe and common psychiatric disorders
with high rates of self-harm and suicide attempts (Hegerl et al., 2013). The causes of
major depressive disorder are not well understood. A diverse contribution of genetic,
neurochemical and environmental factors are involved in the onset and progression of
depression. Besides the common monoamine hypotheses, the diathesis stress model is
another attempt to explain the etiology of depressed behavior (Gold and Chrousos,
2013). Diathesis interacts with the subsequent stress response of an individual,
especially some early life experiences which are known to increase the risk for
depression (Kiejna et al., 2010). Antidepressants initially correct imbalances of
neurotransmitters in the synapse cleft (Mahar et al., 2014; Werner and Coveñas, 2013),
while the therapeutic response may result from above and the downstream adaptive
changes that occur as a consequence of increased neuroplasticity. These subcellular
events include synaptic transmission, gene expression, neuronal morphological
changes and many other molecular events in the brain (Kavalali and Monteggia, 2012;
Pilar-Cuéllar et al., 2012; Seo et al., 2014). However, some patients do not tolerate
some of the undesirable effects associated with these agents such as nervousness,
insomnia or sexual dysfunction (Sussman. 1994). Novel targets and new classes of
antidepressant agents are required to improve the therapeutic arsenal for the treatment
of depression. In addition, currently available antidepressants are prescribed for both
moderately and severely depressed patients (Fournier et al., 2010), and for severe
major depression, a combination of antidepressant medication and psychotherapy or
electroconvulsive therapy are usually considered (Oudega et al., 2011; Hollon et al.,
2014). Antidepressants have unusual temporal responses with many agents having a
delayed onset of action since clinical improvement is observed several weeks after
initiation of antidepressant drug and usually patients have to take antidepressants for
months to get a stable maximal improvement (Kirsch et al., 2008; Mitchell. 2006).
Antidepressants require a timescale of minutes to boost the synaptic concentration of
serotonin and/or norepinephrine, whereas the onset of the therapeutic action is usually
a few weeks after the initiation of therapy. The traditional view about the delayed
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onset of current antidepressant action relies on neurobiological effects that develop
slowly under chronic drug treatment, such as alterations of glucocorticoid receptor
systems in patients with depression, and changes of gene and protein expression
related to dendritic spines, production of brain derived neurotrophic factor (BDNF),
adult hippocampal neurogenesis and enhanced synaptic plasticity (Hajszan et al., 2005;
Anacker et al., 2011b; Malberg et al., 2000; Groves. 2007). The pathological
mechanisms of depression need to be further explored and the controversy about the
mechanism of current antidepressant agents to be resolved.
In recent years, the regulation of gene expression has been implicated in the
etiology and treatment of depression; several genes such as BDNF, fibroblast growth
factor receptor 1, NCAM1 neural cell adhesion molecule 1, and
Calcium/Calmodulin-dependent Protein Kinase II have been identified to be of
interest (Groves. 2007; Tochigi et al., 2008). Transcription factor DNA binding
peptides are essential for the regulation of gene expression and are themselves
regulated by phosphorylation and dephosphorylation. For example, phosphorylated
cAMP-response element binding protein (CREB) transcription factor binds to the
regulatory site on the BDNF promoter and increases BDNF protein levels, both of
which have been associated with depression (Breuillaud et al., 2012). Transcription
factors could serve as the intermediates between intracellular signaling cascades and
gene expression, and therefore be involved in the pathophysiology of depression and
represent potential targets for the pharmacotherapy.
Forkhead box O (FoxO) is a transcription factor, which plays a regulatory role in
multiple biological and pathological systems, including the central nervous system
(CNS). Recent discoveries indicate a role for FoxO in the pathogenesis of
depression and other psychiatric disorders (Polter et al., 2009; Weeks et al., 2010;
Zheng et al., 2013). Enhanced neurotrophins or serotonin neurotransmission in animal
brain phosphorylate and inactivate FoxO3a (Zheng et al., 2002; Polter et al., 2009).
BDNF, which is reduced in depression (Karege et al., 2005; Angelucci et al., 2005),
promotes phosphorylation of the FoxO protein (Mojsilovic-Petrovic et al., 209; Zhu et
al., 2004); moreover, FoxO3a-deficient mice display an antidepressant-like behavior
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(Zheng et al., 2002; Polter et al., 2009; Zheng and Quirion, 2004); Furthermore, both
the serotonin-norepinephrine reuptake inhibitor antidepressant venlafaxine and the
mood stabilizer lithium, suppress FoxO3a activity in mouse brain (Wang et al., 2013;
Mao et al., 2007). FoxOs are under the control of neurotransmitters (Liang et al., 2006)
and glucocorticoids(Qin et al., 2014). FoxOs also regulate signals for cellular atrophy
(Jaitovich et al., 2015), cellular morphology (Aranha et al., 2009) and adult
neurogenesis (Zhang et al., 2013) and all of these physiological or pathological
conditions contribute to the development of depression (Borre et al., 2014; Mahar et
al., 2014; Anacker et al., 2013). Although the role of FoxOs in the process of
depression is only beginning to be unveiled, it is reasonable at this time to
hypothesize that FoxO transcription factors will be found to be pivotal mediators in
psychiatric disorders. In this review, cellular signaling cascades responsible for
regulating FoxOs, the possible roles of FoxOs in the development of depression, the
effects of antidepressants on the activity of FoxOs as well as the potential mechanistic
pathways linking major depression and FoxOs will be discussed.
2. Overview of FoxO signaling pathway
Forkhead box (Fox) proteins are a family of transcription factors characterized
by a conserved “forkhead” or “winged helix” DNA binding motif. Foxs bind to the
regulatory sequence of the downstream target genes and play important roles in
regulating the transcription of genes involved in cell growth, proliferation,
differentiation, metabolism, apoptosis and drug resistance (Lam et al., 2013; Accili
and Arden 2004). According to the sequence homology, Fox superfamily genes can be
classified from FoxA to FoxS (Lam et al., 2013). Of the Fox subfamilies, the FoxO
group is one of the most researched subgroups. FoxOs share a conserved
DNA-binding domain, the binding sequence is 5’-TTGTTTAC-3’ (Brent et al., 2008).
In mammals, there are four FoxO homologues, FoxO1, FoxO3a, FoxO4 and FoxO6.
FoxO2 was shown to be same with FoxO3a and FoxO5 is the ortholog of FoxO3a in
the zebra fish (Carter and Brunet, 2007). The activity of FoxO is regulated by
post-translational modification, including phosphorylation, acetylation, methylation,
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ubiquitination and glycosylation (Eijkelenboom and Burgering, 2013; Zhao et al.,
2011). Phosphorylation of FoxO by protein kinases has been extensively studied.
Protein kinase B (Akt), serum/glucocorticoid inducible kinase (SGK), AMP-activated
protein kinase (AMPK), mitogen-activated protein kinases (MAPK), inhibitor of
nuclear factor kappa-B kinase (IKK), cyclin-dependent kinase (CDK) and mammalian
sterile 20-like kinase (MST) are common upstream kinases for FoxO (Boccitto and
Kalb, 2011). Phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway activated by
insulin or growth factors mediates the major regulation of FoxO (woodgett, 2005).
Binding of insulin or other growth factors (such as nerve growth factor, BDNF or
insulin like growth factor 1 (IGF-1) to their receptors leads to the autophosphorylation
of the growth factor receptor and its subsequent activation (Zheng et al., 2002; Zheng
and Quirion, 2004; Zheng and Quirion, 2009). Through regulation via the PI3K/Akt
pathway, many of downstream target genes of FoxO (such as Btg-1, Bim-1, FasL,
MnSOD, p27, PEPCK) are regulated and these gene products play roles in cell
proliferation (p27), differentiation (Btg-1), metabolism (PEPCK) , apoptosis (Bim-1,
FasL) and drug resistance (Wen et al., 2012; van der Vos and Coffer, 2011; Hui et al.,
2008). For example, sustained FoxO3a activation promotes drug resistance by
activating and promoting the expression of ATP-binding cassette sub-family B
member 1, which is a plasma membrane P-glycoprotein that functions as an efflux
pump for various anticancer agents, including doxorubicin (Hui et al., 2008).
The PI3K pathway is a major regulator of FoxOs activity. Akt and SGK are two
key downstream components of the PI3K pathway and both of them recognize the
RXRXXS/T motif. Akt phosphorylates FoxO3a at Thr32, Ser253 and Ser315, while
SGK phosphorylates FoxO3a at Thr32 and Ser315. For FoxO1, Akt phosphorylates it
at Thr24, Ser256 and Ser319, while SGK phosphorylates it at Thr24 and Ser319
(Burgering and Kops, 2002). Phosphorylation of these sites leads to translocation of
FoxOs from the nucleus to cytoplasm and inhibition of transcriptional activity (Chen
et al., 2013; Huang and Tindall, 2007). What is important is that the C terminal of
FoxO6 lacks the Akt phosphorylation site and thus it is constitutively nuclear (Jacobs
et al., 2003). Extracellular regulated protein kinase (ERK) is a downstream
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component of MEK and it has been shown to phosphorylate FoxO3a at Ser294,
Ser344 and Ser425 (Yang et al., 2008), similarly, activation of IKK induces FoxO3a
phosphorylation at Ser644 (Hu et al., 2004). Phosphorylation of FoxO3a by both ERK
and IKK leads to nuclear exclusion and degradation. The serine/threonine kinases p38
and c-Jun N- terminal kinase (JNK) are other two major MAPK pathways relevant to
FoxO function. p38 phosphorylates FoxO3a at Ser7 and promotes the nuclear
translocation and activation of FoxO3a (Ho et al., 2012); JNK may repress the
PI3K/Akt signal pathway, thereby activating FoxO3a indirectly, meanwhile, it may
phosphorylayte FoxO proteins in a direct way (Sunters et al., 2006). FoxOs may also
play a critical role in the regulation of energy homeostasis when phosphorylated by
the AMP-activated protein kinase (AMPK) at six sites (Greer et al., 2009). In contrast
to the effect of the above kinases on FoxOs, MST binds to FoxO3a and
phosphorylates it at Ser207; however, the phosphorylation of this site promotes its
nuclear accumulation and subsequently the expression of proapoptotic genes (Sanphui
and Biswas, 2013). Another interesting example is the role of CDK on FoxOs. CDK1
phosphorylates FoxO1 at Ser249 and enhances the content of FoxO1 in the nucleus
and thus promotes cell death (Yuan et al., 2008), CDK2 phosphorylates FoxO1 at the
same site, however, it leads to the accumulation of FoxO1 in the cytoplasm and the
inhibition of FoxO1 (Huang et al., 2006). Figure 1 summarizes the above pathways
regulating FoxO activity and subcellular localization.
Fig.1. Effects of various upstream regulators on the activity and subcellular localization of
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FoxO. Phosphorylation is one of the most common post-translational modifications. Kinases, such
as Akt, IKK, SGK, ERK1/2 and CDK promote the export from the nucleus and inactivation of
FoxO. While under stress conditions, MST, AMPK, p38MAPK and JNK induce the nuclear
accumulation and activation of FoxO. In the nuclear, FoxO recognizes and binds to FRE (FoxO
response element), activated FoxO thereby regulates the transcription activity of its downstream
targets, which makes it possible to regulate many cellular processes, including proliferation,
differentiation, metabolism, apoptosis and drug resistance.
3. FoxO expression patterns in the brain
FoxO is one of the substrates for Akt which is a pro-survival serine/threonine
kinase. The PI3K/Akt signal pathway plays a critical role in mediating neuronal
survival. FoxO regulates the expression of genes involved in neuronal cell apoptosis
and oxidative stress, such as Bim-1, FasL, Catalase and MnSOD (Brunet et al., 2001a,
Wen et al., 2012). The pattern of protein distribution related to FoxO functions points
to the associated biological functions. Understanding the expression patterns of FoxO
in the CNS should help us to understand the relationship between FoxO and
neurodevelopment, neurodegeneration and potentially neuropsychiatric disorders.
FoxOs are highly expressed in brain areas related to the regulation of mood and stress.
FoxO1, FoxO3a and FoxO4 are each expressed during neurodevelopment and also in
the adult, with distinct patterns ranging from ubiquitous to tissue-specific (Biggs et al.,
2001). Among the FoxO subtypes expressed in brain, FoxO1 is mostly expressed in
the hippocampus and the striatum (Zemva et al., 2012), its mRNA is expressed in part
of the ventral region of the CA3 pyramidal neurons, however, no expression was
observed in the dorsal CA3 neurons (Hoekman et al., 2006). FoxO3a shows the
widest brain expression, whereas FoxO4 is expressed at very low levels in the brain
and a FoxO4 probe did not reveal detectable expression in the adult murine brain
(Salih et al., 2012). FoxO6 is mostly expressed during the developmental stage with a
nuclear-predominant distribution (Jacobs et al., 2003). For FoxO6, both the protein
and mRNA levels are highly expressed during the stage of neuronal development, and
its expression decreases during maturity but then stays relatively constant. In the adult
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brain, FoxO6 protein is expressed abundantly in hippocampus, amygdala and nucleus
accumbens (Salih et al., 2012). Converging evidences suggest that the hippocampal
complex may play a role in the pathology of major depression (Campbells and
Macqueen, 2004). FoxO isoforms also have different patterns of expression in the
hippocampus where FoxO1 is enriched in the dentate gyrus (DG) region of
hippocampus, FoxO3a is present in all hippocampal areas but more highly expressed
in the DG and CA3 regions than in the CA1 region. FoxO6 is enriched in the CA1 and
CA3 hippocampal areas (Hoekman et al., 2006; Furuyama et al., 2000; Jacobs et al.,
2003; Salih et al., 2012). The differential expression patterns suggest that FoxO
isoforms may have specific and perhaps complementary or redundant roles in
different physiological or pathological processes. In conclusion, spatial expression
patterns of FoxO gene family members in the CNS, especially regions related to stress,
implicate their biological functions in stress-related behavior regulation.
4. FoxOs regulate the behavioral manifestation of depression
The role of FoxOs in psychiatric disorders has recently drawn more attention
even though the data in this area are somewhat limited at this time. FoxOs, especially
FoxO6, are expressed abundantly in hippocampus, amygdala and nucleus accumbens
which are important brain areas involved in aversive and rewarding responses to
emotional stimuli (Accili and Arden, 2004; Hoekman et al., 2006). Thus FoxOs could
mediate the inability to experience pleasure and lack of motivation that predominate
in many patients with depression (Berton and Nestler, 2006). The subregional
distributions of FoxOs could predict their roles in the regulation of mood and emotion.
In a case-control association study in a Brazilian population, FoxO3a emerged as an
gene candidate involved in bipolar disorder and related behaviors. Three
single-nucleotide polymorphisms within the FoxO3a gene (rs1536057, rs2802292 and
rs1935952) were associated with bipolar disorder (Magno et al., 2011). Mood-related
behavioral disturbance, such as depression, is highly related to stress (Krishnan and
Nestler, 2008). In a learned helplessness animal model, which is a commonly used
model to mimic human depression (Muller et al., 2011), inescapable shocks
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significantly reduced the phosphorylation of FoxO3a and induced the nuclear location
of FoxO3a in the cerebral cortex, interestingly, learned helplessness behavior was
markedly diminished in FoxO3a-deficient mice(Zhou et al., 2012). This research
provides evidence that depression activates FoxO3a. These results was consistent with
the previous report that FoxO3a influences behavioral processes linked to anxiety and
depression and FoxO3a-deficient mice show a significant antidepressant-like behavior,
but these animals didn't exhibit changes in general locomotor activity tested by open
field test (Polter et al., 2009), suggesting that FoxO3a is a transcriptional target for
mood disorder treatment. In contrast, a study using a knockout (KO) mause model
suggested that FoxO1 KO mice displayed reduced anxiety (Polter et al., 2009).
Recently, disrupted rhythms are observed in psychiatric disorders, including
depression (Emens et al., 2009). Association of Clock gene and major depressive
disorder has also been suggested (Germain and Kupfer, 2008). Although the detailed
etiologies still need to be unraveled, it is evident that there is a strong relationship
between major depression and circadian disruption (Karatsoreos, 2014). Interestingly,
clock is a transcriptional target of FoxO3a and the insulin-FoxO3a-Clock signaling
pathway plays a key role in the modulation of circadian rhythms, for instance, knock
down of FoxO3a dampens circadian amplitude (Chaves et al., 2014; Zheng et al.,
2007). These studies revealed an important new role for FoxOs in the regulation of
depressive behavior.
BDNF is a well known regulator involved in the pathophysiology of mood
disorders and a recognized upstream effector of FoxOs. The role of BDNF in
depression is well characterized. Depression, at least in its severe form, is associated
with reduced neuronal plasticity and lower levels of BDNF, while antidepressants,
such as fluoxetine, could reactivate BDNF-mediated neuronal plasticity (Castrén and
Rantamäki, 2010). BDNF reduces FoxO transcriptional activity through activation of
TrkB and downstream kinases including Akt, which is a candidate susceptibility gene
related to schizophrenia (Emamian et al., 2004). The link between Akt and depression
was also provided by both genetic studies and postmortem data (Hsiung et al., 2003;
Pereira et al., 2014). In response to BDNF, active Akt phosphorylates and inactivates
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FoxOs (except for FoxO6, which is constitutively nuclear) by facilitating their
translocation out of the nucleus (Wen et al., 2012). In both invertebrate and vertebrate
brain, FoxOs can be phosphorylated and inactivated by serotonin selective reuptake
inhibitors or exogenous serotonin via a PI3K/Akt-dependent mechanism (Polter et al.,
2009; Liang et al., 2006). All of data suggests that downregulation or inactivation of
FoxOs are highly related to antidepressant-like effects.
5. Antidepressants regulate the activities of FoxOs
The classical view of depression is that a functional deficit in neurotransmitters,
particularly decreased levels of serotonin and noradrenaline, are associated with the
clinical symptoms of depression. Serotonin could be viewed as a regulator of the
insulin/IGF-1-FoxO pathway in stress physiology and modulation of FoxO by
serotonin represents a conserved feature of stress physiology. Acute stressful life
events can lead to the recurrence of episodes of major depression and chronic stress is
strongly associated with both onset and recurrence of depression (Kessler, 1997;
Risch et al., 2009). Studies of C. elegans showed that serotonin-deficient mutants
exhibited DAF-16 (the homologues of FoxO) nuclear accumulation in constitutive
physiological stress states, while treatment with exogenous serotonin directly or with
fluoxetine, an antidepressant known to increase synaptic levels of endogenous
serotonin, prevented DAF-16 nuclear accumulation in wild-type animals under
aversive conditions (Liang et al., 2006). This result was confirmed by experiments
showing that serotonin and fluoxetine can partially suppress DAF-16 nuclear
accumulation in wild type animals exposed to hypergravity in C elegans (Kim et al.,
2007). These observations suggest that individual behavior and physiological or
psychiatric responses to the environment in animals are likely accompanied by the
changes of the subcellular location/function of FoxO protein.
The tricyclic antidepressant agent, imipramine, is a monoamine-regulating
antidepressant. Chronic treatment with imipramine for 28 days in mice caused
appreciable increases in phosphorylated FoxO1 (Ser256), FoxO3a (Ser253) and Akt
(Thr308) in the cerebral cortex, hippocampus and striatum, but no changes in the level
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of total FoxO1, FoxO3a and Akt were observed (Polter et al., 2009). Our previous
results also indicated that the FoxO3a subtype in PC12 cells could be inactivated by
the antidepressant venlafaxine via PI3K/Akt pathway. Venlafaxine, on one hand,
induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and on the
other hand reversed the reduction of phosphorylated Akt and FoxO3a and the nuclear
translocation of FoxO3a induced by corticosterone (Wang et al., 2013). Lithium,
another well known therapeutic drug in the treatment of mood disorder, reduced
FoxO3a transcriptional activity, gene expression and protein levels in both the cytosol
and nucleus, and this effect was independent of Akt (Mao et al., 2007). Moreover, this
effect of lithium was observed in SH-SY5Y neuroblastoma cells and mouse brain
(cortex and hippocampus) after relevant lithium treatments, which indicate that this
effect is likely therapeutically relevant (Mao et al., 2007). Amphetamine is a
compound which can increase the concentration of dopamine in the synaptic gap and
thus induce hyperactivity, reversal of its action by lithium is used to model mania in
bipolar disorder. A study from our lab indicated that pretreatment of animals with
lithium prevented an amphetamine-induced decrease in striatal phosphorylated Akt
and FoxO1 levels (Zheng et al., 2013). Lithium also attenuated amphetamine-induced
locomotor activity and decreased prepulse inhibition (Zheng et al., 2013). The
modulation by lithium of FoxO and its upstream kinases (such as Akt) may be
relevant to the treatment of neuropsychiatric disorders. Since FoxO3a can be
regulated by BDNF-induced Akt activation, and phosphorylated by antidepressants,
we hypothesize that FoxO3a is a candidate transcription factor that plays a role in
mood disorders, including depression. Further studies are needed to elucidate the role
of FoxO transcription factors in the neuropathology and treatment of mood disorders.
6. FoxO as a regulator of serotonin and norepinephrine signaling
Decreased or abnormally low levels of serotonin and norepinephrine in the
synaptic cleft is traditionally viewed as a common cause of mood disorders, including
depression. These neurotransmitters play their roles by binding and activating their
specific receptors. With the exception of the 5-HT3 receptor, which is a ligand-gated
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ion channel, all other 5-HT receptors and adrenergic receptors are seven
transmembrane G protein-coupled receptors (GPCRs) whose binding to serotonin or
norepinephrine activates several intracellular second messenger cascades. Some of
these cascades are related to FoxOs. For example, the serotonin 2A receptor
(5-HT2AR) is highly expressed on pyramidal neurons in the frontal cortex and has
been implicated in several psychiatric disorders, including depression. The density of
5-HT2R is higher in depressive patients than that in normal persons. Higher 5-HT2A
binding in the prefrontal cortical region has been shown to be associated with greater
gene expression in depression and youth suicide (López-Figueroa et al., 2004).
Antidepressants (such as mirtazapine and mianserin) could occupy 5-HT2AR, block
its role and augment the clinical response to SSRIs (Celada et al., 2004). Serotonin
binds to 5-HT2AR and stimulates Akt phosphorylation in the frontal cortex and in
primary cortical neurons through the activation of a PI3K/Akt cascade (Schmid and
Bohn, 2010). FoxO transcription factors are downstream targets of PI3K/Akt, which
is mainly regulated by receptor tyrosine kinases (such as IGF-1 receptor) and GPCRs.
Serotonin is a regulator of the insulin/IGF-1 pathway in stress physiology and
exogenous 5HT can suppress the nuclear accumulation of FoxO in wild-type animals
under stress (Liang et al., 2006). Moreover, in the peripheral system, serotonin also
influences the physiological actions of FoxO, for example, serotonin enhances the
proliferation of hepatocellular carcinoma cells through upregulation of FoxO3a
(Liang et al., 2013) . Duodenum-derived serotonin is a critical regulator of bone mass
during the process of bone formation, and importantly FoxO1 mediates this effect
(Kode et al., 2012). High circulating serotonin levels prevent the association of
FoxO1 with CREB, resulting in suppressed osteoblast proliferation (Kode et al., 2012).
These results demonstrate that FoxO acts as an endogenous mediator of serotonin
signaling which may have consequences for the role of FoxOs in psychiatric disorders
associated with altered serotonin metabolism.
As mentioned above, the 5-HT3 receptor is a ligand-gated ion channel whereas
other receptors for serotonin are GPCRs. Serotonergic GPCRs can be classified on the
basis of their associated Gα proteins into Gs-protein coupled receptors (5-HT4, 5-HT6,
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5-HT7), Gi-protein coupled receptors (5-HT1, 5-HT5), and Gq/G11-protein coupled
receptors (5-HT2). As for norepinephrine receptors, the adrenergic α1 receptor is a Gq
coupled receptor whereas the adrenergic α2 is a Gi coupled receptor. Activation of
Gs-protein coupled receptors leads to activation of adenylate cyclase and an increase
in cellular levels of cAMP, while activation of Gi-protein coupled receptors results in
decreased levels of cAMP. cAMP is a second messenger important in many biological
processes, including mood/emotional regulation. Downstream effectors of cAMP
include cAMP-dependent protein kinase (PKA) and exchange factor directly activated
by cAMP (Epac). Deficits in cAMP/PKA or cAMP/ERK signaling are viewed as one
of the mechanisms for the behaviorial symptoms in depression (Breuillaud et al., 2012;
Musazzi et al., 2010). There is interplay between the PI3K/Akt/FoxO and cAMP/PKA
signaling pathways (Chen et al., 2007). FoxO1 is a direct substrate for PKA and PKA
phosphorylates FoxO1 at Thr24, Ser256, and Ser319, three known Akt
phosphorylation sites (Lee et al., 2011). Epac is an exchange protein activated by
cAMP. Both Epac and PKA induce ERK phosphorylation, and ERK in turn
phosphorylates FoxO3a at Ser294, Ser344 and Ser425 (Yang et al., 2008), and FoxO1
at Ser246, Ser284, Ser295, Ser326, Ser413, Ser415, Ser429, Ser467 and Ser475
(Asada et al., 2007) resulting in degradation of FoxO proteins (Fig.2). These results
show that the binding of ligands or agonists to the serotonin or norepinephrine
receptors results in the alteration of intracellular cAMP, which affect the cAMP/PKA
or cAMP/ERK signal pathway, and might influence the biological functions of
FoxOs.
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Fig.2. FoxO as a regulator of serotonin signaling. 5-HT receptor is a G protein coupled
receptor, when 5-HT binds, the receptor activates the coupled G protein, which can diffuse along
the membrane surface and directly activate PI3K/Akt signal pathway, leading to inactivation of
FoxO proteins. On the other hand, 5-HT receptor may also stimulate adenylyl cyclase/PKA and
Epac/ERK1/2 signal transduction, both PKA and ERK1/2 enhance the phosphorylation of FoxO,
which lead to inactivation of FoxO. Catalytic subunit of PKA translocates into nuclear and
promote the activation of CREB, which is also highly related with depression.
7. FoxO as an effector of Hypothalamic-pituitary-adrenal axis
The activated hypothalamic-pituitary-adrenal (HPA) axis stimulates the secretion
of adrenocorticotrophic hormone (ACTH) from the pituitary, which ultimately
promotes the secretion of glucocorticoids from the adrenal cortex. Depression has
been associated with hyperactivity of the HPA axis and increased levels of
glucocorticoid in the serum where continuously high glucocorticoid levels attenuate
the responsiveness and number of glucocorticoid receptors on hippocampal granule
cells thus leading to impaired negative feedback suppression of glucocorticoid
secretion and an even higher level of circulating corticosteroid (Anacker et al., 2011a;
Anacker et al., 2011b; Raison and Miller, 2003). A schematic presentation of how the
amygdala and the hippocampus regulate the HPA axis and the stress response is
presented in Figure 3. Recent evidence suggests that FoxO plays a crucial role in the
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pathophysiological hyperactivity of the HPA axis (Lutzner et al., 2012； Lutzner et al.,
2012). Glucocorticoids activate FoxO signaling, and FoxO signaling is a major
contributor to the mechanism of glucocorticoid-induced muscle atrophy (Sandri et al.,
2004; Zhao et al., 2007). FoxO1 and FoxO3a expression (both mRNA and protein) are
up-regulated by glucocorticoid treatment in hippocampal neurons and muscle cells
(Anacker et al., 2011a; Poulsen et al., 2011). Induction of FoxO3a expression requires
glucocorticoid receptor-binding steroids and is reversed by concomitant treatment
with the glucocorticoid receptor antagonist RU-486 (Lutzner et al., 2012). Importantly,
recent data indicate that FoxO3a is a direct glucocorticoid receptor target, as there are
two potential glucocorticoid response elements within the promoter region of FoxO3a.
These glucocorticoid hormones may induce transcriptional activation of FoxO3a
directly (Lutzner et al., 2012). These results indicate that glucocorticoids regulate
FoxO3a on a transcriptional level. Further evidence indicates that glucocorticoids
regulate FoxO3a post-translationally. Glucocorticoids induce the expression of SGK,
a serine/threonine kinase and activation and phosphorylation of SGK (Thr-256,
Ser-422) is dependent upon PI3K activity (Buse et al., 1999). Activated SGK can
promote cell survival through phosphorylating FoxO3a at sites Thr-32 and Ser-253
(Brunet et al., 2001b). When given in relatively high doses, glucocorticoids inhibit
PI3K/Akt signaling, thereby reducing the phosphorylation of FoxO (Wang et al., 2013;
Stitt et al., 2004). Moreover, consistent with the notion that overload of
glucocorticoids is crucial to the development of depression (Anacker et al., 2013;
Anacker et al., 2011b), antidepressant treatment antagonizes the role of
glucocorticoids (Budziszewska et al., 2000; David et al., 2009) and additionally
increases the level of phosphorylated FoxO3a and PI3K/Akt (Wang et al., 2013).
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Fig. 3. Regulation of HPA axis by the amygdala and hippocampus in normal and stress
conditions. The corticotropin-releasing hormone neurons are regulated by both the amygdala and
the hippocampus. Activation of amygdala promotes the release of cortisol through HPA axis.
Mineralocorticoid receptors and glucocorticoid receptors are abundant in the hippocampus, both
of which respond to and regulate the level of cortisol in the serum by glucocorticoid negative
feedback. In stress condition, inappropriate activation of the amygdala extensively stimulates the
HPA axis, resulting in high level of cortisol in the body. Chronic exposure of hippocampus to
excessive glucocorticoid leads to neuronal loss and morphological atrophy, and thus the negative
feedback becomes weaken or disrupted, which leads to much higher level of cortisol. Chronic
stress induces nuclear localization of GR, which binds to glucocorticoid response
element (GRE) and promotes the transcription of FoxO, GR may also activate SGK
and subseqently inhibit the activity of FoxO.
8. FoxOs regulate neuronal morphology and possibly mediate neuronal atrophy
Neuroimaging studies with magnetic resonance imaging scanning demonstrated
that compared with healthy individuals, depressed patients had an increased volume
of the lateral ventricles and smaller volumes of the basal ganglia, thalamus,
hippocampus, and frontal lobe (Arnone et al., 2012). The decreased cerebral size may
be attributed to the loss and atrophy of neurons. In fact, clinical and preclinical studies
have revealed that prolonged stress and major depression are associated with
decreased neuronal synapses, neuronal atrophy of the PFC and the hippocampus
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(Duman and Aghajanian, 2012; Ota et al., 2014; Sheline et al., 2003; Sheline et al.,
1996). Compared with normal controls, depressed patients showed decreased cortical
thickness, neuronal size, and neuronal and glial densities in the prefrontal cortical
regions (Rajkowska et al., 1999), but the molecular mechanisms underlying these
morphological alterations have not yet been identified.
FoxO transcription factors are important mediators of the effects of
IGF-1/PI3K/Akt signaling. Withdrawal of IGF-1 causes reduced size of white matter
structures in brain due to a decreased numbers of axons (Beck et al., 1995), while
overexpression of IGF-1 leads to increased brain size due to an increase in cell size
and apparently in cell number (Carson et al., 1993). As FoxOs are important key
mediators of insulin and IGF-1 signaling (Kennedy et al., 2013), it is possible that
FoxOs mediates the effect of IGF-1 in this process. Since overexpression of FoxO3a
leads to reduced brain size and a decrease in neural progenitor number
(Schmidt-Strassburger et al., 2012) and consistently, decreased FoxO activity has been
reported to result in larger brain size and increased neural progenitor proliferation
(Paik et al., 2009; Renault et al., 2009). Akt, one of the pivotal upstream kinases
regulating the function of FoxO, has been shown to play a role in regulating cell size,
a response which shares mechanisms with cellular atrophy or hypertrophy.
Constitutively active Akt increases muscle fiber size and prevents denervation
atrophy in regenerating and adult rat muscle (Pallafacchina et al., 2002). In 2004, Stitt
et al., (Stitt et al., 2004) reported that the IGF-1/PI3K/Akt pathway plays an important
role in preventing skeletal muscle atrophy by inhibiting the expression of
muscle-specific ubiquitin ligases MAFbx and MuRF1. Interestingly, this effect
involves Akt-mediated inhibition of the FoxO transcription factors as mutation of
FoxO1 attenuated the activation of Akt thereby preventing Akt-mediated inhibition of
muscle atrophy(Stitt et al., 2004). This research extended the function of FoxO to the
regulation of cellular atrophy and the role of FoxO in cell atrophy and hypertrophy
has since been extensively studied. As in skeletal muscle, overexpression of FoxO3a
also caused a significant reduction in cardiomyocyte size in mouse hearts in vivo and
the induction of atrogin-1 by FoxO3a accounts for this effect (Skurk et al., 2005). The
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role of FoxO transcription factors in mediating the muscle atrophy has been widely
studied (Castets and Ruegg, 2013; Sanchez et al., 2014; Lee et al., 2012), however,
the specific role of FoxO in neuronal atrophy is largely unknown. The four FoxO
members found in humans, FoxO1, FoxO3a, FoxO4, and FoxO6, are all expressed in
the CNS (Biggs et al., 2001; Salih et al., 2012). The IGF-1/PI3K/Akt signaling
pathway is a key pathway for neuronal homeostasis (Rafalski and Brunet, 2011a).
FoxOs are the classic downstream targets of the IGF-1/Akt pathway and both
IGF-1/PI3K/Akt and FoxO have been identified in the regulation of cell atrophy.
From this perspective, it is likely that FoxO mediates neuronal atrophy in the CNS
and this effect is related to the etiology of depression. This speculation is worthy of
further investigation potentially leading to a better understanding of the precise
functions of FoxO transcription factors in the regulation of neuronal cell size and this
might lead to the development of completely novel therapeutic approaches to the
prevention or limitation of the morphological alterations that prevail in ageing and
pathological states, such as depression and schizophrenia .
9. FoxOs play a inhibitory role in neurogenesis and synaptogenesis
Preclinical evidence showed that adult hippocampal neurogenesis may contribute
to the mechanism of antidepressant drug action and BDNF is probably involved in
this effect (Malberg et al., 2000; Guilloux et al., 2013; Sairanen et al., 2005). In fact
BDNF has been implicated in regulating adult neurogenesis in the subgranular zone of
the DG and is important for the regulation of the basal level of neurogenesis in adult
mice (Lee et al., 2002; Waterhouse et al., 2012). FoxOs are downstream effector
molecules of BDNF since BDNF activates a variety of signaling cascades, including
PI3K/Akt, Ras/MAPK and cAMP/PKA pathways and activation of these pathways
phosphorylates and inhibits the functioning of FoxOs (Kwon et al., 2011; de la
Torre-Ubieta and Bonni, 2011). The regulatory effects of BDNF on FoxOs and its
target genes play a significant role in the BDNF-mediated neurogenesis, neuronal
survival and plasticity (Zhu et al., 2004).
FoxO transcription factors coordinately regulate diverse pathways to govern
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neural stem cell or progenitor cell homeostasis in the brain (Paik et al., 2009; Renault
et al., 2009). Given the importance of neural stem cells and progenitor cells for the
generation of new neurons, the role of FoxO in the regulation of neurogenesis from
neural stem cells has attracted attention. Genetic manipulation producing a transgenic
mice expressing a constitutively active FoxO3a leads to mice having smaller brains
accompanied with a loss of neurons in the olfactory bulbs, the cortex, the striatum,
thalamic regions, and most notably the DG (Schmidt-Strassburger et al., 2012). Both
the olfactory bulbs and the DG region are the sites for neurogenesis in adult, whilst
neurogenesis assessed in adult FoxO3−/− and FoxO3+/+ mice revealed that FoxO3a
deficiency in vivo led to an appreciable increase in the production of new neurons in
the olfactory bulbs (Webb et al., 2013). However, the role of FoxOs in adult
hippocampal neurogenesis remains to be investigated. FoxOs are classic downstream
substrate of Akt (Zheng et al., 2002), these findings were quite consistent with earlier
investigations showing that inhibition of 3-phosphoinositide-dependent protein kinase
1/Akt signaling reduces neurogenesis in neural progenitor cells, whereas constitutive
activation of Akt or phosphatase and tensin homolog deletion promotes neurogenesis
(Oishi et al., 2009; Gregorian et al., 2009). These results support the argument that
FoxO negatively regulates neurogenesis in the brain.
Reduced synaptogenesis could be observed in the prefrontal cortex and
hippocampus of patients with depression whereas normal synptogenesis restores the
synapse connections in the brain that may deteriorate under stress and depression
(Bambico and Belzung, 2013). Mammalian target of rapamycin (mTOR) is a
ubiquitous protein kinase involved in protein synthesis and synaptogenesis. Activation
of mTOR by PI3K/Akt promotes protein synthesis and synaptogenesis (Ayuso et al.,
2010). However, FoxOs play a role in protein degradation (White et al., 2013).
Moreover, it has been shown that FoxO1 inhibits mTOR signaling and protein
synthesis. Activation of constitutively active FoxO1 reduces the phosphorylation of
4E binding protein 1 (Thr-37/46) and by consequence the phosphorylation of the
downstream protein p70S6 kinase leading ultimately to an attenuation of protein
production (Southgate et al., 2007). This inhibition of protein synthesis affects
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proteins (such as post-synaptic density protein 95 and synaptophysin) involved in
synapse formation. On the other hand, recent studies suggest that the rapid-acting
antidepressant and synaptogenic effects of ketamine are dependent upon mToR
activity in the medial prefrontal cortex (Li et al., 2010). This finding fits our
hypothesis well. As mentioned previously, FoxOs inhibit mTOR signaling (Southgate
et al., 2007), under this condition, inactivation of FoxOs may be beneficial for the
antidepressant effect of ketamine. Microtubule architecture in neurons is an essential
element in the regulation of neuronal morphology and motility as well as
synaptogenesis (Conde and Caceres, 2009). FoxO loss-of-function models display
increased stability of microtubule and overexpression of wild-type FoxO moderately
destabilizes microtubules (Nechipurenko and Broihier, 2012). Thus, it is conceivable
that FoxOs negatively regulate synaptic microtubule stability and thus negatively
regulate synaptogenesis. The roles of FoxOs in the regulation of cellular atrophy,
neurogenesis and synaptogenesis are depicted schematically in Figure 4.
Fig. 4. The roles of FoxOs in the regulation of cellular morphology. Neurotrophic factors or
growth factors, such as BDNF or IGF-1, play a pivotal role in the maintenance of normal cellular
morphology. IGF-1 binds to its receptor and activates several signaling pathways. FoxOs are the
classic downstream targets of IGF-1/PI3K/Akt pathway. Both IGF-1/PI3K/Akt and FoxOs are
involved in the regulation of cell size. Activated Akt phosphorylates and inactivates FoxO proteins,
it also phosphorylate and activate mTOR, which subsequently phosphorylates eukaryotic
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translational initiation factor 4E binding protein 1 (4E-BP1), 70kDa ribosomal protein S6 kinase
(p70S6K), and thereby promotes protein translation. Active FoxOs suppress the phosphorylation
of 4E-BP1 and p70S6 kinase and thus limit protein synthesis. In addition, FoxO transcription
factors induce the expression of atrophy- related ubiquitin ligase atrogin-1 and cause cellular
atrophy, this effect possibly account for the neural atrophy implicated in the process of depression.
FoxO may also suppress neurogenesis through inhibiting Wnt signaling. Furthermore,
FoxOs limit the stability of microtubules, all of which contribute to the morphological changes
(such as neuronal atrophy, decreased neurogenesis and synaptogenesis) occurring in the depressed
individuals.
Down-regulated adult hippocampal neurogenesis and synaptogenesis in the
prefrontal cortex and hippocampus have been linked to major depressive disorder.
Chronic stress leads to decreased neuronal/progenitor cell proliferation within the
specific region of the brain, neuronal spines and neuronal plasticity are also reduced
in this condition (Bambico and Belzung, 2013). Interestingly, this process is reversible.
Administration of antidepressants will produce an increase in the number of
new-borne neurons within the hippocampus (Malberg et al., 2000; Guilloux et al.,
2013; Sairanen et al., 2005). The observation that current antidepressant drugs
promote adult hippocampal neurogenesis provides a much stronger evidence on this
link (Mahar et al., 2014; Zunszain et al., 2013). These findings suggest a link between
depression and adult neurogenesis in the hippocampus and, as discussed previously,
many antidepressants repress the activation of FoxO. In this context, it can be
speculated that the inactivation of FoxO3a by the PI3K/Akt signaling pathway
achieves a more potent induction of adult hippocampal neurogenesis and
synaptogenesis.
10. Conclusions and Prospective
FoxOs are recently discovered transcription factors which play a role in the onset
or duration of psychiatric disorders. Results from cellular studies and animal models
support the idea that FoxOs are potential mediators in the pathogenesis of depression
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(Polter et al., 2009; Wang et al., 2013; Liang et al., 2006). Given the considerations to
target FoxO proteins as a novel therapeutic strategy for major depression, it becomes
essential to further investigate whether specific FoxO family members should be
targeted. Activation and upregulation of upstream molecules of FoxOs, including
growth factors (such as BDNF, fibroblast growth factor and IGF-1), receptor tyrosine
kinases, Akt and ERK1/2 produce beneficial effects against depression (Shi et al.,
2012; Evans et al., 2004; Krogh et al., 2014; Mikoteit et al., 2014; Musazzi et al.,
2010). In this condition, over inhibition of FoxOs through activation of its upstream
molecules increases the risk of cancer should be taken into consideration. The roles of
FoxO transcription factors in major depression are summarized schematically (Fig. 5).
However, the possibility of FoxOs and their signaling pathways being potential
therapeutic targets in depression requires considerable experimental exploration and
validation. Their nature as transcription factors and the difficulty to target them
directly suggest that targeting the signaling pathways rather than the FoxOs
themselves may be preferred strategy towards efficacious therapeutic agents. At
present, most of the information about FoxOs is derived from cellular and animal
models. Direct data from individuals diagnosed with major depression are still in
great need. It will be desirable that future work should be carried out to study the
alteration of FoxOs in depressive individuals and post mortem brain tissues. Studies
of the genetic linkage of FoxOs and depression also provide evidence to support a role
of FoxOs in this very important area of human pathophysiology.
Fig. 5. The roles of FoxOs in major depression. Chronic stress causes imbalances of
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neurotransmitters (such as 5-HT and NE), decreased production of growth factors (such as BDNF
and IGF-1) and hyperactivation of HPA axis. The interaction of neurotransmitters with their
postsynaptic receptors and binding of growth factors to their receptor tyrosine kinases (RTKs)
inactivate FoxOs through cAMP/PKA, PKC, PI3K/Akt or MEK/ERK signaling. Hyperactive HPA
axis promotes the nuclear location and activation of FoxOs. Released glucocorticoid also bind to
the GRE in the promoter of FoxOs and enhance the production of FoxOs. As a result, chronic
stress leads to the activation of FoxO, which inhibits neurogenesis/synaptogenesis and promotes
neuronal atrophy. Consequently, all of these cause behavioral manifestations related to depression.
FoxOs have been linked to skeletal muscle atrophy and control of cardiomyocyte
size in numerous models (Sandri et al., 2004; Skurk et al., 2005) so it is reasonable to
speculate that the Akt-FoxO pathway may participate in neuronal atrophy, impairment
of synaptogenesis/neurogenesis and control of brain size in depression. Currently
there is little evidence to support this intriguing possibility, but it is worth studying the
effect of FoxOs on the regulation of neuronal cell size and exploring the mechanisms
of decreased cerebral volume in depressed individuals. However, there are always
benefits and short comings to everything, what we should keep in mind is that since
FoxOs affect cell size, there are possible unwanted side effects of targeting FoxO in
treatment of depression, such as muscle hypertrophy. Moreover, abnormalities
observed in major depression most commonly occur in the raphe nuclei, nucleus
accumbens, anterior cingulated cortex, amygdala and hippocampus (Goffer et al.,
2013; Tripp et al., 2011; Underwood et al., 1999; Andrus et al., 2012), but we still
need to elucidate whether the change of FoxOs and their related signal pathways
could be altered in region specific manner.
Despite the usefulness of currently available antidepressant medications, the
limitations of both efficacy and tolerability are nonetheless evident. A better
understanding of the underlying neurobiology and neuropathophysiology of
depression will help us to discover novel targets for pharmacological interventions. In
this review, we have outlined the involvement of FoxOs and related molecules in the
pathogenesis of depression. Targeting FoxO proteins might attenuate neuronal
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apoptosis and play a neuroprotective effects in the central nervous system, which
might be considered beneficial to block degenerative disorders. However, whether or
not this can yield therapeutic target and the generation of a novel class of agents for
the treatment of major depression will depend upon further research which reveals the
importance of FoxOs in the physiological and particular processes of major
depression.
Acknowledgements
This research was supported by National Natural Science Foundation of China
(No. 81301099, No. 81373384 and No. 31371088), Natural Science Foundation of
Guangdong Province (No. S2013040014202), China Postdoctoral Science Foundation
(No. 2013M542192), and the Science and Technology Development Fund (FDCT) of
Macao (FDCT 021/2015/A1).
Conflict of Interest Disclosures
The authors declare no conflict of interest.
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Highlights
FoxO transcription factors regulate the behavioral manifestation of depression
Antidepressants regulate the phosphorylation/activities of FoxOs
FoxOs are regulated by serotonin and norepinephrine receptor signaling and HPA axis
FoxOs induce cell atrophy and this effect may affect neuronal morphology