Neuronal plasticity: A link between stress and mood disorders

Psychoneuroendocrinology (2009) 34S, S208—S216 

REVIEW 

Neuronal plasticity: A link between stress and 

mood disorders 

Francesca Calabrese, Raffaella Molteni, Giorgio Racagni, Marco A. Riva * 

Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy 

Received 17 April 2009; received in revised form 22 May 2009; accepted 23 May 2009 

KEYWORDS 

BDNF; 

Depression; 

Stress; 

Antidepressant; 

Glucocorticoid receptors; 

Resilience 

Contents 

available at www.sciencedirect.com 

journal homepage: www.elsevier.com/locate/psyneuen 

Summary Although stress represents the major environmental element of susceptibility for 

mood disorders, the relationship between stress and disease remains to be fully established. In 

the present article we review the evidence in support for a role of neuronal plasticity, and in 

particular of neurotrophic factors. Even though decreased levels of norepinephrine and serotonin 

may underlie depressive symptoms, compelling evidence now suggests that mood disorders are 

characterized by reduced neuronal plasticity, which can be brought about by exposure to stress at 

different stages of life. Indeed the expression of neurotrophic molecules, such as the neurotrophin 

BDNF, is reduced in depressed subjects as well as in experimental animals exposed to 

adverse experience at early stages of life or at adulthood. These changes show an anatomical 

specificity and might be sustained by epigenetic mechanisms. 

Pharmacological intervention may normalize such defects and improve neuronal function 

through the modulation of the same factors that are defective in depression. Several studies have 

demonstrated that chronic, but not acute, antidepressant treatment increases the expression of 

BDNF and may enhance its localization at synaptic level. Antidepressant treatment can normalize 

deficits in neurotrophin expression produced by chronic stress paradigms, but may also alter the 

modulation of BDNF under acute stressful conditions. In summary, there is good agreement in 

considering neuronal plasticity, and the expression of key proteins such as the neurotrophin BDNF, 

as a central player for the effects of stress on brain function and its implication for psychopathology. 

Accordingly, effective treatments should not limit their effects to the control of 

neurotransmitter and hormonal dysfunctions, but should be able to normalize defective mechanisms 

that sustain the impairment of neuronal plasticity. 

# 2009 Elsevier Ltd. All rights reserved. 

1. Neuronal plasticity and psychiatric illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S209 

2. Stress and susceptibility to mood disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S209 

3. Neurotrophic factors as markers of plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S210 

* Corresponding author. Tel.: +39 02 50318334; fax: +39 02 50318278. 

E-mail address: M.Riva@unimi.it (M.A. Riva). 

0306-4530/$ — see front matter # 2009 Elsevier Ltd. All rights reserved. 

doi:10.1016/j.psyneuen.2009.05.014

Stress, neurotrophic factors and depression S209 

4. BDNF: a neurotrophin with multiple sites of regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S210 

5. Neurotrophic factors in depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S211 

6. Modulation of BDNF expression by stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S211 

7. Modulation of BDNF by antidepressant treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S212 

8. Antidepressant treatment modulate stress-induced changes of BDNF . . . . . . . . . . . . . . . . . . . . . . . . . . . S212 

9. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S214 

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S214 

1. Neuronal plasticity and psychiatric illness 

Neuronal plasticity refers to the ability of the nervous system 

to respond and adapt to environmental challenges and 

encompasses a series of functional and structural mechanisms 

that may lead to neuronal remodelling, formation of 

novel synapses and birth of new neurons. However, in a 

broader sense, neuronal plasticity is intimately linked to 

cellular responsiveness and may therefore be considered 

an index of the neuronal capability to adapt its function to 

a different demand. Failure of such mechanisms might 

enhance the susceptibility to environmental challenges, such 

as stress, and ultimately lead to psychopathology. That is to 

say that the brain, or more specifically, some brain structures 

or circuits, may become more vulnerable by loosing progressively 

(or suddenly) the ability to adapt and maintain their 

homeostasis. The manifestation of such vulnerability can be 

quite different according to the pathologic condition and 

may lead to overt degeneration (as occurring in neurodegenerative 

disorders) or to more subtle changes, leading to 

functional impairment, which represents a feature of psychiatric 

illness. 

During the last few years it has indeed become apparent 

that several psychiatric conditions, such as mood disorders, 

are associated with deficits or impairment of neuronal plasticity 

(Castren, 2005; Krishnan and Nestler, 2008; Pittenger 

and Duman, 2008). Although for many years depression has 

been linked to abnormalities in monoaminergic neurotransmission, 

it is now well accepted that this condition is characterized 

by profound alterations of brain function and 

responsiveness. Hence depressed subjects display an inability 

to cope or adapt to the environment and may be more 

vulnerable to challenging experiences. These abnormalities 

may be intimately linked with neuronal plasticity and the 

ability to modulate a cascade of events from intracellular 

signaling mechanisms to gene expression. 

Although the individual susceptibility threshold to environmental 

events may be genetically determined, it is believed 

that life events occurring during brain development may be 

critical for later psychopathology. Traumatic experiences 

occurring early in life may herein disrupt the correct program 

of maturation and eventually impact on brain function leading 

to a deterioration of neuronal plasticity. Indeed the brains of 

depressed subjects show structural abnormalities and reduced 

expression of several markers for neuronal function and viability, 

among which neurotrophic factors seem to be playing a 

pivotal role (aan het Rot et al., 2009; Sheline et al., 2003). 

These new concepts imply a reconsideration of the 

mechanisms that may be relevant for clinical achievements. 

In agreement with the well-known delay for therapeutic 

responses, psychotropic drugs, should be able to restore 

these defective systems around a physiological set point in 

order to alleviate symptoms and reduce the susceptibility to 

environmental challenges. In a word, these treatments might 

contribute to maintain stability. 

We will discuss neuronal plasticity in the context of stressrelated 

situations and mood disorders by focusing on neurotrophic 

factors, and in particular the neurotrophin brainderived 

neurotrophic factor (BDNF), although several other 

mechanisms should also be taken into account, since most of 

these systems are interrelated and may represent different 

facets of the same condition. 

2. Stress and susceptibility to mood 

disorders 

Stress represents the major precipitating factor in mood disorders. 

It may be inferred that affected subjects have a 

different threshold for stress susceptibility, which means that 

mechanisms that are required to cope with stress can be 

altered or less functional. The effects of stress on brain 

function depend on the timing and duration of the adverse 

experience. As already mentioned, adverse events early in life 

can be particularly relevant for later psychopathology since 

they will impact on structures that are not fully matured. 

According to the period when the adverse experience is taking 

place, different structures can be affected. Another critical 

factor is the duration of the stressful experience according to 

the concept of allostasis and allostastic load (McEwen, 2000). 

Indeed the same mediators or system involved in the adaptation 

to acute challenges, can also participate in pathological 

effects determined by prolonged repetitive exposure to stressful 

conditions. For example within the hippocampus, a mild 

stress can enhance learning and memory (Luine et al., 1996), 

whereas chronic or severe stressors, as well as high doses of 

glucocorticoid, have detrimental effects on hippocampus 

dependent memory (Sapolsky, 2003) and impair LTP (Kim 

and Diamond, 2002). Sustained stress or glucocorticoid levels 

can lead to neuronal atrophy, in hippocampus and prefrontal 

cortex, whereas other regions, such as the amygdala, can 

become hypertrophic (Sapolsky, 2003). These changes resemble 

functional and structural alterations found in depressed 

subjects (aan het Rot et al., 2009; Sheline et al., 2003), 

suggesting that they may indeed represent a long-lasting 

consequence of stress on a vulnerable individual. 

Several mechanisms can be responsible for these alterations. 

First of all there is a well-established dysfunction of the 

hypothalamus—pituitary—adrenal (HPA) axis, according to 

which altered expression and function of glucocorticoid 

receptors in the hypothalamus and the hippocampus may 

lead to reduced feed-back that is responsible for elevated 

levels of circulating glucocorticoids and protracted responses

S210 F. Calabrese et al. 

to stressors. However the effects of stress on brain structure 

and function, and its possible relationship to depression 

susceptibility, may also be mediated by an impairment of 

neuronal plasticity. According to this possibility stress can 

modulate a series of mechanisms that are important for 

neuronal resilience. If under acute conditions some of these 

mechanisms can be ‘protective’ or may activate ‘defensive’ 

pathways, more protracted adverse experiences can produce 

an impairment of such mechanisms that will ultimately lead 

to reduced neuronal plasticity. Within this context, neurotrophic 

factors may play a central role. Some of these 

factors, such as the neurotrophin BDNF, are valuable marker 

of neuronal plasticity and may therefore represent an important 

element in order to understand the relationship 

between stress and mood disorders. We will recapitulate 

evidence for the involvement of trophic molecules, in particular 

BDNF, in stress and major depression. 

3. Neurotrophic factors as markers of 

plasticity 

Network construction and reorganization, which are the main 

processes involved in neuroplasticity, are regulated by the 

level and pattern of synaptic activity generated in the nervous 

system. The discovery that excitatory neurotransmitters can 

stimulate new gene transcription by triggering an influx of 

calcium into postsynaptic suggested a mechanism by which 

stimulus-evoked neuronal activity might lead long-lasting 

changes in the structure and function of the nervous system. 

Specifically, activity-dependent gene expression occurs when 

the calcium influx induced by synaptic activation initiates 

calcium-dependent signaling cascades that drive gene expression 

through the activation of specific transcription factors 

(West et al., 2002). Among the activity-regulated genes 

responsive to neuronal activity, neurotrophic factors (NTFs), 

and in particular the neurotrophin family, play an important 

role. In fact, besides their classical role in supporting neuronal 

survival, NTFs finely modulate all the crucial steps of network 

construction, from neuronal migration to experience-dependent 

refinement of local connections (Poo, 2001). These functions 

were first reported based on the observation that during 

the development of the nervous system neuron survival 

depends on the limited amount of specific NTFs secreted by 

target cells (Huang and Reichardt, 2001). However, it is now 

well established that NTFs are important mediators of neuronal 

plasticity also in adulthood where they modulate axonal 

and dendritic growth and remodelling, membrane receptor 

trafficking, neurotransmitter release, synapse formation and 

function (Lu et al., 2005). The neurotrophin BDNF has emerged 

as crucial mediator of neuronal plasticity, not only because it is 

abundant in brain regions that are particularly relevant for 

plasticity, but because it shows a remarkable activity-dependent 

regulation of its expression and secretion (Bramham and 

Messaoudi, 2005), suggesting that it might indeed bridge 

experience with enduring change in neuronal function. 

4. BDNF: a neurotrophin with multiple sites 

of regulation 

BDNF is a member of the neurotrophin family that has an 

important role in development as well as in adult neuronal 

plasticity. A number of studies carried out in the last few 

years have demonstrated that BDNF has a sophisticated 

organization in terms of transcriptional, translational and 

posttranslational regulatory mechanisms. 

With regard to BDNF transcription, its gene consists of nine 

5 0 untranslated exons (some of which are enriched in the 

CNS), each linked to individual promoter regions, and a 3 0 

coding exon (IX), which codes for the BDNF pre-protein amino 

acid sequence (Aid et al., 2007). The transcription of each 

exons is driven by separate promoters in turn controlled by an 

array of signaling mechanisms, including calcium, CREB, 

MEK, MeCP2, CaMKII and hormones (Lu, 2003; Molteni 

et al., 2009a; Zhou et al., 2006). Furthermore it has been 

demonstrated that the transcription of specific BDNF splice 

variants is controlled by a variety of epigenetic mechanisms, 

including DNA methylation and posttranslational modifications 

of histones (Lubin et al., 2008; Roth et al., 2009). The 

regulation of specific promoters causes the temporal and 

spatial expression of specific BDNF transcripts (Lauterborn 

et al., 1996), some of which can undergo trafficking and 

targeting to dendrites (Chiaruttini et al., 2008), a process 

that may also be influenced by the 3 0 untranslated region 

(UTR) of the neurotrophin (An et al., 2008; Ghosh et al., 

1994). 

BDNF is initially synthesized as proform that can either be 

cleaved into the mature neurotrophin or transported to the 

plasma membrane and released in an unprocessed manner. 

Several matrix metalloproteases (MMP) as well as plasmin are 

responsible for extracellular cleavage of the neurotrophin, 

whereas furin and specific proconvertases control its intracellular 

processing (Schweigreiter, 2006). Differently from 

other neurotrophins, BDNF can be secreted through a constitutive 

as well as a regulated pathway. 

Interestingly, the prodomain of the neurotrophin contains 

a single nucleotide polymorphism leading to a Val/Met substitution, 

which results in a less efficient sorting of BDNF 

protein into the regulated secretory pathway (Chen et al., 

2006). Although, this polymorphism has been associated with 

the risk of psychiatric disorders, not all studies support these 

findings, and the overall evidence for an association of BDNF 

Val/Met polymorphism with disease risk is still weak (Petryshen 

et al., 2009). 

The prodomain interacts with sortilin that promote an 

appropriate configuration of proBDNF. This, in turn, allows 

the sorting motif in the mature domain of BDNF to interact 

with carboxypeptidase E (CPE), and, therefore, to sort BDNF 

into the regulated secretory pathway. Thus, BDNF protein can 

be packaged into secretory vescicles (Lessmann et al., 2003) 

that are present in both axon terminals (presynaptic site) and 

dendrites (postsynaptic site) of glutamatergic neurons (Fawcett 

et al., 1997), from which the neurotrophin can be 

released in a Ca ++ -dependent manner. Upon release, proBDNF 

and mBDNF have divergent activities, since the former binds 

with high affinity to p75 NTR leading to apoptosis, whereas 

mBDNF binds to TrkB receptors promoting cell survival (Lu 

et al., 2005). Activated receptors in general are capable of 

triggering a number of signal transduction cascades including 

the mitogen-activated protein kinase (MAPK) pathway, the 

phosphatidylinositol 3-kinase (PI3K) pathway and the phospholipase 

C-g (PLC-g) pathway (Huang and Reichardt, 2001; 

Huang and Reichardt, 2003), which can also be used to 

monitor neurotrophin release and receptor activation.


Interestingly, as we will see in the next sections, most of 

these events, including transcription, translation and synaptic 

storage of the neurotrophin, can be modulated by pharmacological 

treatments or environmental manipulations, 

suggesting that the BDNF system offers multiple sites for 

modulation, which lead to changes of neuronal plasticity that 

will ultimately affect the function and structure of selected 

brain regions. 

5. Neurotrophic factors in depression 

Several papers have demonstrated, with different 

approaches, the relationship between neurotrophic factors 

and depression. 

First of all, postmortem studies suggest that the expression 

of selected neurotrophic molecules is altered in the 

brain of depressed patients. Accordingly Evans and co-workers 

have shown a decreased expression of several genes 

associated with the fibroblast growth factor family (Evans 

et al., 2004). In particular the expression of FGF-1, FGF-2, 

and their receptors FGFR2 and FGFR3, is decreased throughout 

the limbic system, whereas the levels of FGF-9 and FGF- 

12 appear to be up-regulated (Evans et al., 2004). Reduced 

BDNF expression (mRNA as well as protein) has been detected 

in the hippocampus and prefrontal cortex of postmortem 

brains from suicide victims (Dwivedi et al., 2003). These 

changes were associated with a significant down-regulation 

of TrkB, the high affinity receptor of the neurotrophin (Dwivedi 

et al., 2003). Moreover, consistent data suggest that 

serum BDNF levels are reduced in depressed subjects, an 

effect that can be normalized by antidepressant treatment or 

electroconvulsive therapy (ECT) (Bocchio-Chiavetto et al., 

2006; Sen et al., 2008). 

Large support for a role of neurotrophic factors, and 

related deficits of neuronal plasticity, in mood disorders 

comes from animal studies, either through the knockout of 

genes encoding for neurotrophic factors or through exogenous 

administration of recombinant proteins. 

Microinjection of FGF-2 into the lateral ventricle of adult 

rats at the end of day 1 of the forced swim test induces less 

depression-like behaviour on the 2nd day of the test (Turner 

et al., 2006). Other neurotrophic molecules, such as VEGF 

(vascular endothelial growth factor) or VGF (nonacronymic), 

mimic the action of antidepressants in behavioural tests like 

the forced swim test or learned helplessness (Hunsberger 

et al., 2007; Thakker-Varia et al., 2007; Warner-Schmidt and 

Duman, 2008). Similar finding have been observed with BDNF, 

whose infusion into the brain results in antidepressant-like 

behaviour (Shirayama et al., 2002). 

BDNF’s role in depression has also been extensively studied 

in mutant mice. Lack of BDNF is not sufficient to produce 

a depressive phenotype (Chourbaji et al., 2004), but the 

neurotrophin is required for the behavioural response to 

antidepressant since the selective deletion of the BDNF gene 

in the hippocampal dentate gyrus, as well as the impaired 

function of its high affinity receptor TrkB, prevents behavioural 

responses to antidepressant drugs (Adachi et al., 

2008; Monteggia et al., 2004; Saarelainen et al., 2003). 

However, BDNF appears to have an opposite role in the 

ventral tegmental area (VTA): its over-expression at this 

level determines a depression-like phenotype, whereas animals 

with a selective knockout of BDNF in the VTA are 

protected from the depressive effects produced by the social 

defeat stress (Berton et al., 2006). These data suggest that 

the role of BDNF in mood disorders and stress responsiveness 

is complex and strictly anatomical-dependent. 

Further, as we will discuss in more detail later in this 

article, antidepressant drugs can up-regulate the expression 

of neurotrophic factors, an effect that might normalize 

defective systems or increase neuronal plasticity through 

alternative strategies. In fact ECT and antidepressant treatments 

increased, in addition to BDNF (see later in the 

review), the expression for different neurotrophic molecules, 

including FGF-2, VEGF and VGF (Maragnoli et al., 

2004; Newton et al., 2003). 

6. Modulation of BDNF expression by stress 

A modulation of BDNF by stress was originally shown several 

years ago (Smith et al., 1995). Since than, evidence has been 

produced demonstrating the complex outcome of stress on 

the BDNF system. Because epidemiological studies have 

shown that stressful episodes in early life can increase the 

risk to develop depression (Heim et al., 2004), several 

authors have investigated the expression of BDNF in animal 

models that reproduce exposure to adverse life events. 

These paradigms are based on the exposure of pregnant 

dams to repetitive stress (prenatal stress) or rely on the 

disruption of mother—pup interaction early in life (maternal 

separation). As previously mentioned, the susceptibility to 

such events may depend upon the type and timing of the 

manipulation. Indeed we have shown that strong stressors, 

such as a 24 h maternal separation on postnatal day 9 can 

reduce BDNF expression in the rat hippocampus (Roceri 

et al., 2002), although more protracted manipulations during 

gestation or the early phase of postnatal life do not produce 

significant changes on hippocampal BDNF levels (Fumagalli 

et al., 2004; Koo et al., 2003; Roceri et al., 2004). 

Conversely, the length of the manipulation appears to be 

more important than the timing for changes that might occur 

at cortical level. Prenatal stress as well as repeated maternal 

separation determine a significant reduction of BDNF levels in 

prefrontal cortex of adult animals (Fumagalli et al., 2004; Koo 

et al., 2003; Roceri et al., 2004), whereas a single maternal 

deprivation did not elicit any change on cortical neurotrophin 

expression (Roceri et al., 2002). Hence developmental events 

can have enduring effects on BDNF expression that, based on 

its role in information processing as well as on cognition, may 

contribute to the persistent changes on brain function and 

their relative contribution to psychopathology. 

The long-lasting nature of neurotrophin changes appears 

to be due epigenetic mechanisms. A recent study has demonstrated 

that early maltreatment (exposure of infant rats to a 

stressed ‘‘abusive’’ mother 30 min daily during the first 

postnatal week) elicited a reduction of BDNF mRNA levels 

in prefrontal cortex of adult offspring, which was associated 

with an increased methylation of the Bdnf gene on specific 

promoters (Roth et al., 2009). These results are of extreme 

interest since they could provide a molecular basis for enduring 

changes in neuronal plasticity that are associated with a 

reduced ability to turn on the transcription of activity-regulated 

genes, such as the neurotrophin BDNF. 

As we have mentioned, the expression of BDNF is also 

significantly affected by stress at adulthood, although the


final outcome depends on several variables, particularly the 

duration of stress and the time elapsed between the end of 

the stressful experience and the sacrifice. 

Acute stressors can produce a rapid facilitation of the 

BDNF system. In fact a significant and transient increase of 

BDNF mRNA levels has been observed in the rat (Marmigere 

et al., 2003) as well as in the prefrontal and cingulate 

cortex of rats (Molteni et al., 2001) andinthefrontallobe 

of mice (Molteni et al., 2009a) exposed to an acute 

restraint stress. 

We have recently shown that an acute stress (restraint or 

swim) can also regulate the subcellular localization of the 

neurotrophin, with a significant increase of the mature form 

of the neurotrophin in the synaptic compartment (Molteni 

et al., 2009a). The synaptic increase of mBDNF in response to 

the acute stress may be part of a cellular ‘defensive strategy’ 

aimed at increasing the pool of the mature neurotrophin 

that, upon release, might interact with its high affinity 

receptor TrkB and promote synaptic function and cell survival 

(Bramham and Messaoudi, 2005; Chao et al., 2006). Interestingly 

the increased synaptic levels of BDNF after stress are 

not observed in animal with a compromised function of 

glucocorticoid receptors (Molteni et al., 2009b), which represent 

a good model for susceptibility to depression (Ridder 

et al., 2005), suggesting that indeed rapid changes in BDNF 

under challenging conditions may reflect an active response 

strategy to preserve neuronal homeostasis (McEwen, 2008). 

Moreover, it has been recently demonstrated that glucocorticoids 

can also activate trkB receptor tyrosine kinases in vivo 

and in vitro, leading to neuroprotective effects (Jeanneteau 

et al., 2008), suggesting a further mechanism of integration 

between glucocorticoid hormones and neurotrophins. 

If the rapid increase of BDNF expression following a single 

stress may represent a short-term protective mechanism, a 

prolonged stressful experience may have a detrimental 

effect on neuroplasticity, an observation supported by the 

overall negative impact of chronic stress on BDNF expression 

at hippocampal and cortical level. The initial observation of 

Smith et al. (1995) reporting reduced BDNF expression in the 

rat hippocampus after chronic immobilization stress has been 

confirmed by several subsequent studies (Nair et al., 2007; 

Roceri et al., 2002; Vollmayr et al., 2001). Additionally, 

stress-induced down-regulation of hippocampal BDNF 

expression was observed not only after physical–—but also 

following psychological stress (Rasmusson et al., 2002). We 

found reduced BDNF mRNA levels after different paradigms 

of chronic stress in rat prefrontal cortex (Fumagalli et al., 

2004; Roceri et al., 2004) and in mouse frontal cortex 

(Fumagalli et al., 2003). Although the exact mechanism by 

which prolonged stressful experiences regulate BDNF is still 

unknown, the involvement of hormonal and neurotransmitter 

systems, has to be taken into consideration (Joca et al., 2007; 

Molteni et al., 2009a). 

As previously mentioned for developmental manipulations, 

also chronic stress in adult life can alter the expression 

of BDNF, and in particular of some of its transcripts, through 

epigenetic mechanisms. Indeed, Tsankova and collaborators 

have shown that chronic defeat stress down-regulated total 

hippocampal BDNF mRNA levels, primarily through a 

decrease of BDNF exon IV and VI. Such effect was paralleled 

by an increased dimethylation of histone H3 at their relative 

promoters (Tsankova et al., 2006). 

Furthermore a prior history of stress can alter the pattern 

of changes produced by adult-onset stress on BDNF expression. 

For example, chronic immobilization stress reduced 

BDNF levels in the prefrontal cortex of ‘normal’ rats, while 

increasing its gene expression in prenatally stressed rats 

(Fumagalli et al., 2004). Similarly acute stress is not able 

to alter BDNF in rats previously exposed to MD (Nair et al., 

2007; Roceri et al., 2002). 

7. Modulation of BDNF by antidepressant 

treatment 

Since depression is characterized by a reduction of neuronal 

plasticity, which can be produced as a consequence of 

exposure to stress at different stages of life, it may be 

inferred that effective pharmacological treatments should 

be able to correct or normalize such deficits in order to 

achieve functional recovery. Indeed, speaking of depression, 

a key question has always been why therapeutic 

responses with antidepressants could only be achieved after 

at least 2—3 weeks of treatment, whereas their synaptic 

effects occur without any significant delay. Hence, during 

the last decade it has become well accepted the idea that 

this delay is required in order to produce neuroadaptive 

mechanisms that may enhance neuronal plasticity and resilience 

(Castren, 2005; Kozisek et al., 2008; Pittenger and 

Duman, 2008). 

Along this line of reasoning, several studies have shown 

that BDNF may mediate the therapeutic action of antidepressants 

(Berton and Nestler, 2006; Groves, 2007; Martinowich 

et al., 2007).TheexpressionofBDNFincreasesinthe 

hippocampus in response to repeat but not acute treatment 

with major classes of antidepressants (Calabrese et al., 

2007; Castren et al., 2007; Russo-Neustadt and Chen, 

2005). Despite the well accepted effects of antidepressant 

drugs on BDNF expression, during the last 5 years, it has 

become apparent that this modulation can occur at several 

levels. Transcriptional changes can be due to the selective 

modulation of BDNF transcripts (Calabrese et al., 2007; 

Russo-Neustadt et al., 2004), an effect that may be related 

to the modulation of specific transcription factors. Since 

some BDNF mRNA species can undergo dendritic targeting 

(Chiaruttini et al., 2008), these changes may also affect the 

subcellular distribution of the neurotrophin. Indeed we have 

shown that chronic treatment with the novel antidepressant 

duloxetine increases the levels of mBDNF in the synaptic 

compartment (Calabrese et al., 2007) a mechanism that can 

be relevant for the control of the local release of the 

neurotrophin. Furthermore antidepressant treatment can 

also change the levels and the activation of TrkB, the high 

affinity receptor of BDNF, and its signaling (Duman et al., 

2007; Fumagalli et al., 2005; Saarelainen et al., 2003; 

Wyneken et al., 2006). 

8. Antidepressant treatment modulate 

stress-induced changes of BDNF 

Since stress is a major causative factor in depression, it is 

expected that antidepressant drugs could modulate stress 

responsiveness and susceptibility, which is altered in affected 

individuals.


First of all antidepressants can regulate the HPA axis, 

whose function is altered in stress and mood disorders. 

Indeed, it has been found that different stressors decrease 

glucocorticoid receptor (GR) levels in the hippocampus (Chen 

et al., 2008; Meyer et al., 2001), while antidepressant treatment 

can up-regulated their expression (Przegalinski and 

Budziszewska, 1993). Moreover, antidepressant treatment 

is able to alter the stress responsiveness in term of translocation 

of glucocorticoids receptors from the cytoplasm to the 

nucleus. We demonstrated that chronic antidepressant treatment 

increase the nuclear GR levels after an acute stress 

(Molteni et al., 2009a), in accordance with a previous study 

showing that antidepressant increase dexametasone-induced 

GR traslocation (Pariante et al., 1997). In a recent study it has 

been shown that chronic treatment with different antidepressants 

normalizes hippocampal alterations of GR levels 

due to prenatal manipulation (Szymanska et al., 2009). Moreover, 

the levels of FKBP51, a GR co-chaperon that retains GR 

in the cytoplasm, are restored in the prefrontal cortex of the 

same animals. These results suggest that GR and FKBP51 may 

represent key molecules in the alteration of HPA axis seen in 

depressed patients. Alterations of GR expression and function 

have also been reported in human cells and some of these 

changes may be normalized by antidepressant treatment 

(Carvalho and Pariante, 2008). 

While the studies mentioned above suggest that prolonged 

treatment with antidepressant drugs have a positive impact on 

neuronal plasticity, an important point is to understand if and 

how antidepressants could correct stress-induced modifications 

or, eventually if they may alter stress responsiveness. 

With regard to the first issue, it has been demonstrated that 

antidepressant treatment can normalize the reduced expression 

of BDNF following chronic stress. For example chronically 

venlafaxine administration is able to restore BDNF levels and 

neurogenesis that are reduced by after an immobilization 

stress (Xu et al., 2004). Similarly, prolonged treatment with 

imipramine normalizes behavioural alterations in the chronic 

social defeat stress protocol while restoring reduced levels of 

the neurotrophin (Tsankova et al., 2006). Both stress and 

antidepressant treatment may alter BDNF expression through 

epigenetic mechanisms. However while prolonged stress may 

repress BDNF transcription through a hypermethylation of 

histone proteins that lead to a more ‘closed’ chromatin state, 

chronic imipramine increases H3 histone acetylation in the 

promoter regions of exon IV and exon VI, which may overcome 

the repressing changes leading to an open chromatin conformation 

(Tsankova et al., 2006). These studies provide a good 

example of the possibility that disease-related factors (stress) 

and drug treatments may exert their effects on the same 

protein although not through overlapping mechanisms. 

Since the concept of neuronal plasticity implies that adaptive 

changes are set in motion in response to ‘external’stimuli, 

it is expected that antidepressants should not only improve 

compromised neuronal plasticity by affecting the expression of 

key proteins, but they may also modulate the responsiveness of 

these systems under challenging conditions. Accordingly, we 

have recently shown that antidepressant drugs do not only 

modulate BDNF expression under basal conditions, but can also 

alter its responsiveness under challenging circumstances. In 

fact we found that total BDNF expression was slightly increased 

by chronic duloxetine treatment and further enhanced when 

antidepressant-treated rats were exposed to a short swim 

stress (Molteni et al., 2009a). The antidepressant treatment 

was able to affect the stress modulation of BDNF exon VI, 

whereas exon IV was regulated by stress independently from 

the pharmacological treatment. Moreover, we found that the 

subcellular trafficking of the neurotrophin after stress was 

significantly affected by duloxetine treatment. In fact 

only animals that were chronically injected with the antidepressant 

showed a significant increase of synaptosomal 

mBDNF levels when exposed to the acute challenging condition 

(Molteni et al., 2009a). These data suggest that chronic 

antidepressant treatment can affect cellular resilience not 

only by increasing the expression of ‘protective’ proteins, but 

also by altering the coping ability under potential ‘threatening’ 

situations. 

Figure 1 Mechanisms underlying the impact of stress or depression on the BDNF system and the potential effects of antidepressant 

drugs. Stress can reduce the expression of the neurotrophin through epigenetic (1), transcriptional (2 and 3) and translational mechanisms 

(4). On the other hand antidepressant drugs can restore normal levels of the neurotrophin by different mechanisms including: increase 

histone acetylation or reduced DNA methylation (5) at specific BDNF promoters; increase transcription of different exons (6 and 7); 

elevated synthesis and trafficking of BDNF protein (8); stimulation of protein release and increase receptor interaction (9).


9. Concluding remarks 

In summary, the data herein reviewed suggest a close link 

between stress, neuronal plasticity and major depression. We 

believe that a putative mechanism through which stress can 

alter the susceptibility to mood disorders is the modulation of 

neuroplastic molecules, such as neurotrophins. Accordingly, 

antidepressant drugs are able to normalize defective 

mechanisms that sustain the impairment of neuronal plasticity 

and can increase neuronal resilience (Fig. 1). The understanding 

of these adaptive mechanisms may lead to the 

identification of molecular targets for the development of 

novel and more effective drugs. 

Conflict of interest 

None. 

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