European Neuropsychopharmacology 14 (2004) S497 S502 www.elsevier.

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Molecular mechanisms of neuroplasticity and pharmacological implications: the example of tianeptine

Bruce S. McEwena,*, Sumantra Chattarjib
a

Harold and Margaret Milliken Hatch-Laboratory of Neuroendocrinology Rockefeller University, New York, NY 10021, USA b National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India

Abstract The hippocampal formation, which expresses high levels of adrenal steroid receptors, is a malleable brain structure that is important for certain types of learning and memory. This structure is also vulnerable to the effects of stress hormones which have been reported to be increased in depressed patients, particularly those with severe depression. The amygdala, a structure that plays a critical role in fear learning, is also an important target of anxiety and stress. Certain animal models of depression involve application of repeated stress. Repeated stress promotes behavioral changes that can be associated with these two brain structures such as impairment of hippocampus-dependent memory and enhancement of fear and aggression, which are likely to reflect amygdala function. At a cellular level, opposite responses in the hippocampus and amygdala are observed, namely, shrinkage of dendrites in hippocampus and growth of dendrites in the lateral amygdala, involving in both cases a remodeling of dendrites. Furthermore, stress-induced suppression of neurogenesis has been noted in dentate gyrus. At a molecular level, the effects of repeated stress in the hippocampus involve excitatory amino acids and the induction of the glial form of the glutamate transporter. Chronic treatment with the antidepressant tianeptine may prevent these effects in hippocampus and amygdala. D 2004 Elsevier B.V. and ECNP. All rights reserved.
Keywords: Glutamatergic transmission; Stress; Depression; Amygdala; Dendritic remodelling; Tianeptine

1. Introduction Findings in recent years suggest that brain plasticity is a very important aspect of depression. Structural magnetic resonance imaging (MRI) performed in the brains of depressed patients has shown reduction in the volume of gray and white matter of the prefrontal cortex, reduction in hippocampal volume and decreased volumes in the amygdala. Functional changes in cerebral blood flow and glucose metabolism were also noted in hippocampus and amygdala (reviewed in Drevets, 2000a,b; Miguel-Hidalgo and Rajkowska, 2002). In particular, the work of Sheline et al (Sheline et al., 1996, 1999, 2003) showed a reduced hippocampal volume in depressed patients, a correlation between the duration of depression and volume loss, and a recovery of the volume after antidepressant treatment. Furthermore, they showed that atrophy of the hippocampus
* Corresponding author. Tel.: +1 212 327 8624; fax: +1 212 327 8634. E-mail address: mcewen@mail.rockefeller.edu (B.S. McEwen).

in major depression worsened with repeated episodes. This, along with evidence that hippocampal volume is not reduced in the first episode of major depression (MacQuenn et al., 2003), suggests that the hippocampal atrophy was the result of the illness rather than the cause. Moreover, on postmortem histopathology, reductions in neuronal size and/or decreased density of glial cells in the orbitofrontal, dorsolateral, and subgenual prefrontal cortex were found in the brains of patients with major depression (Manji et al., 2003; Rajkowska et al., 1999). The association between brain changes, the occurrence of depression, and the action of antidepressants has been studied by using animal models. In animals, depression is represented by repeated stress paradigms; these paradigms have shown to be reliable models of depression in rodents (Willner, 1997) as well as in tree shrews, a prosimian species with an evolutionary relationship to primates that has been shown to be a suitable model for studying the neurophysiological consequences of chronic psychosocial stress (Fuchs et al., 1996).

0924-977X/$ - see front matter D 2004 Elsevier B.V. and ECNP. All rights reserved. doi:10.1016/j.euroneuro.2004.09.008

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Fig. 1. The repeated stress of confrontation between an intruder and a dominant tree shrew cause dendrites of neurons in the CA3 region of the hippocampus to become shorter and less branched. As a result, cognitive processes that depend on the hippocampus such as certain types of learning and memory are impaired. Circulating stress hormones are believed to mediate these changes, along with the excitatory amino acid neurotransmitters produced by the hippocampal neurons (reprinted from Magarinos et al., 1996).

A growing body of evidence has shown that chronic stress can cause hippocampal damage (McEwen, 1999). The first studies showed how stress and stress hormones produced significant dendritic remodeling in CA3 pyramidal neurons. Dendritic remodeling in these neurons is characterized by a reversible shortening and debranching of apical dendrites and is mediated by mechanisms involving high levels of glucocorticoid secretion (Magarinos and McEwen, 1995; McEwen, 1999; Watanabe et al., 1992). Later research has also shown decreased adult neurogenesis in the dentate gyrus (Gould et al., 1997). Dendritic remodeling was also observed in the psychosocially stressed tree shrew (Fig. 1) (Magarinos et al., 1996) and in this animal a stress induced reduction of total hippocampal volume has also been reported (Czeh et al., 2001). Over the past decade, most of the studies have primarly focused on the hippocampus. This brain structure has been shown to be extremely susceptible to stress-related damage and, since it expresses a high level of adrenal steroid receptors, it exerts a negative feedback regulation of the stress response via the hypothalamo-pituitary-adrenal (HPA) axis (Jacobson and Sapolsky, 1991; McEwen, 1999). The inhibitory role of the hippocampus in the regulation of the HPA axis is supported by several studies, and prolonged and severe stress might lead to this control being disrupted. Other limbic structures that are involved in regulating the HPA axis through excitatory inputs, such as the amygdala, are becoming the focus of increasing attention since there is evidence of the critical role of this structure in fear, anxiety, and activation of the HPA axis (Davis et al., 1994; LeDoux,

1995; Pitkanen et al., 1997). Activation of the medial or cortical amygdaloid nuclei elicits corticosterone secretion, and lesions of the central nucleus reduce corticosterone or ACTH responses to restraint and fear conditioning (Davis et al., 1994; LeDoux, 1995; Pitkanen et al., 1997). Moreover, anatomical studies indicate limbic inputs impinging on the paraventricular nucleus (PVN) and the hypothalamic GABA-ergic (GABA, gamma-aminobutyric acid) neurons can be either excitatory from the hippocampus (thereby enhancing GABA-ergic tone) or inhibitory from amygdala (thereby reducing GABA-ergic tone). This in turn implies that while enhanced hippocampal input would suppress the HPA axis activity, enhanced amygdaloid input could have opposite effects on HPA activity (Herman and Cullinan, 1997). Repeated stress produces behavioral changes that can be associated with hippocampus and amygdala: it impairs hippocampus dependent memory (Lowy et al., 1993) but also impairs memory through nonhippocampal mechanisms such as enhanced emotionality (Conrad et al., 1999). There is, therefore, a potential contrasting impact of chronic stress in the hippocampus and amygdala at the behavioral level. This contrasting impact also occurs at the neuronal level: chronic stress has dramatically different effects on dendritic remodeling in hippocampal and amygdaloid neurons and these findings provide new evidence for behaviorally induced structural plasticity on the amygdala of the adult brain (Vyas et al., 2002, 2003). While in the hippocampus chronic immobilization stress elicits significant dendritic atrophy in hippocampal CA3 pyramidal neurons, this stress increases dendritic arborization in the spiny pyramidal and stellate neurons of the basolateral amygdala, which are presumably excitatory projection neurons (Fig. 2). Along with this, there is an increase in anxiety and aggression (Conrad et al., 1999; Vyas et al., 2003; Wood et al., 2003b). An acute effect of stress has also been reported in medial amygdala of mice, along with an increase in anxiety, mediated by tissue plasminogen activator and suggesting that a rapid outgrowth of presynaptic connections may be

Fig. 2. Chronic immobilization stress (2 h per day, 10 days) induces hypertrophy of dendritic arborization in pyramidal neurons of the basolateral amygdala (BLA) in rats. This BLA hypertrophy manifests itself as an increase (right panel, bStressQ) in total dendritic length and branching points compared to control (left panel) neurons. Moreover, this stress-induced dendritic growth is accompanied by an increase in spine-density in BLA pyramidal neurons (inset).

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occurring (Pawlak et al., 2003). This stress-induced dendritic remodeling in hippocampus and amygdala may provide potential cellular substrates for depression.

a model of conditioned freezing (Burghardt et al., 2004). All these effects are likely to reflect amygdala function.

2. Effects of tianeptine on neural plasticity Tianeptine is an antidepressant with proven clinical efficacy (Cassano et al., 1996; Costa e Silva et al., 1997; Kasper and Olie, 2002) and, in addition, it has been reported to alleviate symptoms of anxiety associated with depression, without sedative effects (Ansseau et al., 1996; Lepine et al., 2001). In animal models of depression, tianeptine has been shown to oppose the effects of chronic stress in brain plasticity. In the psychosocially stressed tree shrew, tianeptine prevents two main structural modifications in the hippocampus, namely, a decrease in proliferation rate of granular precursor cells in the dentate gyrus and decrease in hippocampal volume (Czeh et al., 2001). In rodents, tianeptine reverses and prevents the induced atrophy in CA3 pyramidal neurons in the hippocampus after 23 weeks of repeated stress or corticoid administration (Magarinos et al., 1999; Watanabe et al., 1992). In more recent studies in the amygdala, dendritic hypertrophy induced by chronic immobilization stress (CIS) is prevented by tianeptine (S. Chattarji, unpublished observations). As described earlier, it has also been reported that CIS-induced amygdaloid hypertrophy is accompanied by a significant increase in anxiety-like behavior as manifested by a significant decrease in open-exploration in the elevated plus-maze (Vyas et al., 2002, 2003). Interestingly, tianeptine is also effective in preventing this CIS-induced increase in anxiety-like behavior (Pillai et al., 2004). These findings, taken together with the large body of evidence from animal models and human studies, appear to be providing some convergence on the potential efficacy of tianeptine in terms of its actions on structural plasticity in the hippocampus and amygdala, as well as its potential implications for the neural circuitry underlying stress and affective disorders. Further, electrophysiological studies show that while stress impairs prime burst potentiation in hippocampal CA1 region and increases long-term potentiation in basolateral amygdala, tianeptine enhances the induction of synaptic plasticity in hippocampus and does not interfere with the stress-induced changes in amygdala (Vouimba et al., 2003). These structural effects of tianeptine in the amygdala are supported by behavioral data obtained in recent experiments in rodents which show that chronic tianeptine prevents the stress-induced potentiation of aggression and reduces the incidence of stress-provoked aggressive conflicts (Wood et al., 2003a). Furthermore, tianeptine has been shown to be devoid of anxiogenic effects after acute administration and to have anxiolytic properties after repeated administration in

3. Pharmacological mechanisms of these structural modifications Cellular and molecular alterations associated with depression have been studied by modeling the illness through chronic stress in animals. The hippocampus is the region where most of the research has been carried out and elucidating the changes at the hippocampal level can be crucial to understanding what happens in other brain structures implicated in the stress/depression circuitry. There is evidence that the effects of chronic stress involve, besides glucocorticoids, excitatory amino acids. There is a reported increase in extracellular glutamate levels in hippocampus and other brain regions after stress (Lowy et al., 1993, 1995; Maghaddam et al., 1994). Administration of N-methyl-d-aspartate (NMDA) receptor antagonists enhances neurogenesis in the dentate gyrus (Cameron et al., 1995) and prevents the stress- and corticosterone-induced dendritic remodeling (Magarinos et al., 1999; McEwen, 1999). This suggests that the modulation of the glutamatergic system plays a key role in the regulation of synaptic plasticity and that one of the features of antidepressant effects could be to normalize the induced alterations in glutamate function. This normalization could be achieved via mechanisms targeting directly the glutamatergic synapse or indirectly involving other neurotransmitters such as serotonin, noradrenaline, or GABA. Furthermore, studies on the expression of the glial specific excitatory aminoacid transporter GLT1 showed that they are upregulated in the hippocampal CA3 region and dentate gyrus, after stress conditions similar to those that induced dendritic remodeling. This effect was prevented by tianeptine, demonstrating the role of this antidepressant in the regulation of stress-induced changes in the glutamatergic system, perhaps by normalizing synaptic concentrations of glutamate thus elimitating the stimulus for increased GLT1 expression (Reagan et al., 2004). Additional evidence that tianeptine modulates glutamatergic transmission has been provided by electrophysiological studies on the stress-induced alterations at the glutamatergic synapse. These studies have shown that tianeptine normalizes the stress-induced increases in NMDA currents and facilitates glutamate transmission at commissural-associational synapses most likely via an intracellular phosphorylation-dependent postsynaptic mechanism (Kole et al., 2002). Confirmation of the involvement of tianeptine in the phosphorylation state of glutamate receptors is provided by recent research that has explored the ability of the product to regulate the activity of the alpha-amino-3-hydroxyl-5methyl-4-isoxazolepropionate (AMPA) receptor, chosen because of its pivotal role in excitability (Hayashi et al.,

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2003). AMPA receptors can be regulated via phosphorylation at the Ser 831 site via calcium calmodulin-dependent kinase II (CaMKII/PKC) or at Ser 845 via a protein kinase A (PKA) site. Phosphorylation at this site is increased by fluoxetine treatment (Svenningsson et al., 1999). Chronic tianeptine treatment has been shown to increase the phosphorylation of the CaMKII/PKC site Ser 831 in frontal cortex (Svenningsson et al., 2003).

considerable importance with respect to the potential clinical and basic research applications for tianeptine: (1) Modulation of glutamatergic synaptic transmission: Studies described here clearly point towards the need to look beyond the traditional focus of research involving SSRIs, i.e., the serotonergic system. This paradigm shift provides the added advantage of the very large body of evidence on plasticity mechanisms at glutamatergic synapses (e.g., longterm synaptic potentiation and depression). Moreover, there is now a considerable body of new data on the role of NMDA receptors and variations in intracellular calcium and its downstream targets in structural plasticity of dendrites and spines. This in turn provides a very useful point of convergence with the most robust and well-characterized phenotype of stress-induced plasticity, i.e., dendritic remodeling in the hippocampus and amygdala. (2) Plasticity mechanisms in the amygdala: Recent data on the effects of stress on morphological plasticity in pyramidal/stellate neurons in the basolateral amygdala (Vyas et al., 2002) provide a novel cellular substrate for studying the relationship between animal models of stress, anxiety and depression. Pawlak et al. (2003) have also provided new evidence for molecular mechanisms underlying stress-induced plasticity in the amygdala that is closely related to anxiety-like behavior. Moreover, these studies suggest that contrasting patterns of cellular/molecular plasticity mechanisms may underlie the differential effects of chronic stress on the amygdala versus hippocampus. While structural plasticity in the hippocampus may mediate cognitive aspects of behavioral impairments caused by stress, changes in the amygdala are more likely to contribute to the affective aspects of stress disorders. In this context, studies on how tianeptine affects stress-induced plasticity in the hippocampus and amygdala are particularly exciting. (3) Stress and assays of amygdala-dependent behavior: While the hippocampus is undoubtedly involved in symptoms affecting learning and memory, it is unlikely that it accounts for the affective or mood-related symptoms of depression. In spite of the fact that symptoms of anxiety and fear are prominent in many depressed individuals, the amygdala has received relatively little attention in depression. A major barrier to depression research is the lack of validated animal models with a clear understanding of the roles of specific neural circuits and underlying cellular plasticity mechanisms. Consequently, all available animal models of depression rely on one of two principles: actions of known antidepressants or responses to stress. Moreover, very little is known about how identified cell types and their plasticity mechanisms in the amygdala may contribute to specific aspects of standard animal models of depression such as the forced swim test. In contrast, the role of the amygdala in animal models of anxiety and fear is better understood at the level of specific neural circuits and neurotransmitter systems. In this regard, the use of rodent models of fear conditioning (LeDoux, 2000) to study the effects of stress and tianeptine

4. Discussion and conclusion There is now a general consensus that depression is much more complex than just changing levels of monoamines, and that alterations in neural plasticity may be well implicated in the pathophysiology of the illness. Antidepressant treatment is believed to regulate this impaired plasticity and the common pathway could well involve interactive effects between glutamate and other neurotransmitter systems. The research findings discussed in this article point to several new and promising avenues of investigation on the effects of tianeptine on the mechanisms of neural plasticity and their clinical implications. The available data on the mechanism of the antidepressant actions of tianeptine had always been difficult to adapt to the monoaminergic theories of depression: unlike selective serotonin reuptake inhibitors (SSRIs), the compound has been shown to decrease extracellular serotonin levels (Datla and Curzon, 1993) and to be without affinity for the serotonin transporter (Pineyro et al., 1995). The research discussed here points to the fact that the action of tianeptine in the stress/depression circuitry is unique, since by treating the structural changes associated with hippocampus and amygdala it could be expected to ameliorate the memory and emotional deficits that accompany depression. In fact, it has been shown that this trophic activity of tianeptine on plasticity correlates well with its reported effects on preclinical models of anxiety (File and Mabutt, 1991; File et al., 1993a,b) and memory (Conrad et al., 1996; Jaffard et al., 1991; Lebrun and Jaffard, 1993; Luine et al., 1994; Morris et al., 2001) and with the anxious and cognitive symptoms reported in clinics (Ansseau et al., 1996; Guelfi et al., 1989; Lepine et al., 2001; Saletu et al., 1996). The mechanism by which tianeptine achieves its neuroprotective and trophic effects, and therefore, its clinical efficacy, is also unique, since it acts directly by normalizing glutamatergic transmission. This modulation has been shown to be evident in the regions of the brain belonging to the corticolimbic circuitry implicated in mood disorders. Future studies will be directed towards elucidating the exact mechanisms by which tianeptine influences glutamatergic transmission and which, through these actions, is able to alter neuronal structure and connectivity. We will conclude this article by highlighting some of the key features of these new findings that we believe will be of

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(Burghardt et al., 2004) provide a breakthrough in terms of enhancing our insights into the cellular/synaptic underpinnings of affective disorders. Fear conditioning is an animal model of anxiety for which the underlying circuitry has been well characterized down to the level of synaptic and molecular mechanisms (LeDoux, 2000). Therefore, recent studies on the effects of tianeptine on auditory fear conditioning (Burghardt et al., 2004) suggest that this model can be a useful tool in identifying plasticity mechanisms in the amygdala that are responsible for the clinical effects of these drugs. Hence, including animal models of anxiety and fear, in addition to the traditional paradigms of depression, will enhance our ability to further examine the effects of tianeptine on amygdala-dependent processes. (4) Chronic versus acute administration of antidepressants: There are additional issues that have acted as impediments in depression research. First, most animal models of depression utilize acute administration of antidepressants, while their clinical effectiveness requires chronic administration in humans. Second, the acute effects of SSRIs have been reported to be the opposite of the chronic effects. Thus, anxiety is actually enhanced during the early stages of treatment and the anxiolytic effects are manifested only after several weeks of chronic treatment. Findings discussed in this article provide potentially effective ways of overcoming these problems. For example, it has been reported (Burghardt et al., 2004) that acute administration of the SSRI citalopram enhances acquisition of auditory fear conditioning, while treatment with tianeptine has no such acute effect; chronic administration with both reduces acquisition of tone conditioning. These results further reiterate the utility of amygdala-based plasticity and behavioral models in analyzing the differences between short- and long-term antidepressant treatments. In conclusion, armed with a wide spectrum of new data on tianeptine at multiple levels of neural organization, we are in a position to gain significant insight into contrasting mechanisms of plasticity in the amygdala and hippocampus that may contribute to the complex symptoms related to stress, anxiety, and depression. This in turn will help us better understand how the biological cascade that constitutes the stress response fits into a broader network involved in emotional and cognitive information processing functions. References
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