Stress, allostatic load and mental health in Indigenous Australians.

The aim of this narrative review was to demonstrate how the notion of allostatic load (AL) relates directly to the mental health disparities observed between Indigenous and non-Indigenous Australians. We also endeavored to synthesize the results of the limited number of studies examining stress and AL in Indigenous Australians in order to explore the potential public health benefits of the AL concept. A range of literature examining health inequalities, psychosocial determinants of mental illness and AL was explored to demonstrate the applicability of stress biology to the significant mental health burden faced by Indigenous Australians. Furthermore, all original studies indexed in MEDLINE that provided quantitative data on primary stress biomarkers in Indigenous Australians were selected for review. Evidence of hypothalamic-pituitary-adrenal axis dysregulation and increased AL is apparent even in the handful of studies examining stress biomarkers in Indigenous Australians. Urinary, salivary, hair and fingernail cortisol, hair cortisone, urinary epinephrine, heart rate variability and the cortisol awakening response are all AL parameters which have been shown to be dysregulated in Indigenous Australian cohorts. Furthermore, associations between some of these biomarkers, self-perceived discrimination, exposure to stressful life events and symptoms of psychiatric disorders in Indigenous Australians have also been demonstrated. The continued assessment of AL biomarkers and their relationship with past traumas, lifetime stressors and socio-economic factors amongst Indigenous Australians is important to addressing the mental health this population. Measurement of AL biomarkers in a culturally appropriate manner may lead to more targeted preventative measures, interventions and policies, which mitigate the effects of stress at both the individual and societal level.

Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice.

Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene-environment interactions on the translational profile of these cells.

Age and Alzheimer's disease gene expression profiles reversed by the glutamate modulator riluzole.

Alzheimer's disease (AD) and age-related cognitive decline represent a growing health burden and involve the hippocampus, a vulnerable brain region implicated in learning and memory. To understand the molecular effects of aging on the hippocampus, this study characterized the gene expression changes associated with aging in rodents using RNA-sequencing (RNA-seq). The glutamate modulator, riluzole, which was recently shown to improve memory performance in aged rats, prevented many of the hippocampal age-related gene expression changes. A comparison of the effects of riluzole in rats against human AD data sets revealed that many of the gene changes in AD are reversed by riluzole. Expression changes identified by RNA-Seq were validated by qRT-PCR open arrays. Riluzole is known to increase the glutamate transporter EAAT2's ability to scavenge excess glutamate, regulating synaptic transmission. RNA-seq and immunohistochemistry confirmed an increase in EAAT2 expression in hippocampus, identifying a possible mechanism underlying the improved memory function after riluzole treatment.

Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antidepressant.

The adult brain is capable of adapting to internal and external stressors by undergoing structural plasticity, and failure to be resilient and preserve normal structure and function is likely to contribute to depression and anxiety disorders. Although the hippocampus has provided the gateway for understanding stress effects on the brain, less is known about the amygdala, a key brain area involved in the neural circuitry of fear and anxiety. Here, in mice more vulnerable to stressors, we demonstrate structural plasticity within the medial and basolateral regions of the amygdala in response to prolonged 21-day chronic restraint stress (CRS). Three days before the end of CRS, treatment with the putative, rapidly acting antidepressant, acetyl-l-carnitine (LAC) in the drinking water opposed the direction of these changes. Behaviorally, the LAC treatment during the last part of CRS enhanced resilience, opposing the effects of CRS, as shown by an increased social interaction and reduced passive behavior in a forced swim test. Furthermore, CRS mice treated with LAC show resilience of the CRS-induced structural remodeling of medial amygdala (MeA) stellate neurons. Within the basolateral amygdala (BLA), LAC did not reduce, but slightly enhanced, the CRS-increased length and number of intersections of pyramidal neurons. No structural changes were observed in MeA bipolar neurons, BLA stellate neurons or in lateral amygdala stellate neurons. Our findings identify MeA stellate neurons as an important component in the responses to stress and LAC action and show that LAC can promote structural plasticity of the MeA. This may be useful as a model for increasing resilience to stressors in at-risk populations.

Erasure of fear memories is prevented by Nogo Receptor 1 in adulthood.

Critical periods are temporary windows of heightened neural plasticity early in development. For example, fear memories in juvenile rodents are subject to erasure following extinction training, while after closure of this critical period, extinction training only temporarily and weakly suppresses fear memories. Persistence of fear memories is important for survival, but the inability to effectively adapt to the trauma is a characteristic of post-traumatic stress disorder (PTSD). We examined whether Nogo Receptor 1 (NgR1) regulates the plasticity associated with fear extinction. The loss of NgR1 function in adulthood eliminates spontaneous fear recovery and fear renewal, with a restoration of fear reacquisition rate equal to that of naive mice; thus, mimicking the phenotype observed in juvenile rodents. Regional gene disruption demonstrates that NgR1 expression is required in both the basolateral amygdala (BLA) and infralimbic (IL) cortex to prevent fear erasure. NgR1 expression by parvalbumin expressing interneurons is essential for limiting extinction-dependent plasticity. NgR1 gene deletion enhances anatomical changes of inhibitory synapse markers after extinction training. Thus, NgR1 robustly inhibits elimination of fear expression in the adult brain and could serve as a therapeutic target for anxiety disorders, such as PTSD.

Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility.

Why do some individuals succumb to stress and develop debilitating psychiatric disorders, whereas others adapt well in the face of adversity? There is a gap in understanding the neural bases of individual differences in the responses to environmental factors on brain development and functions. Here, using a novel approach for screening an inbred population of laboratory animals, we identified two subpopulations of mice: susceptible mice that show mood-related abnormalities compared with resilient mice, which cope better with stress. This approach combined with molecular and behavioral analyses, led us to recognize, in hippocampus, presynaptic mGlu2 receptors, which inhibit glutamate release, as a stress-sensitive marker of individual differences to stress-induced mood disorders. Indeed, genetic mGlu2 deletion in mice results in a more severe susceptibility to stress, mimicking the susceptible mouse sub-population. Furthermore, we describe an underlying mechanism by which glucocorticoids, acting via mineralocorticoid receptors (MRs), decrease resilience to stress via downregulation of mGlu2 receptors. We also provide a mechanistic link between MRs and an epigenetic control of the glutamatergic synapse that underlies susceptibility to stressful experiences. The approach and the epigenetic allostasis concept introduced here serve as a model for identifying individual differences based upon biomarkers and underlying mechanisms and also provide molecular features that may be useful in translation to human behavior and psychopathology.

Sex, stress and the brain: interactive actions of hormones on the developing and adult brain.

The brain is a target of steroid hormone actions that affect brain architecture, molecular and neurochemical processes, behavior and neuroprotection via both genomic and non-genomic actions. Estrogens have such effects throughout the brain and this article provides an historical and current view of how this new view has come about and how it has affected the study of sex differences, as well as other areas of neuroscience, including the effects of stress on the brain.

Hippocampal gene expression changes underlying stress sensitization and recovery.

Chronic and acute stressors have been linked to changes in hippocampal function and anxiety-like behaviors. Both produce changes in gene expression, but the extent to which these changes endure beyond the end of stress remains poorly understood. As an essential first step to characterize abnormal patterns of gene expression after stress, this study demonstrates how chronic restraint stress (CRS) modulates gene expression in response to a novel stressor in the hippocampus of wild-type mice and the extent to which these changes last beyond the end of CRS. Male C57/bl6 mice were subjected to (1) a forced swim test (FST), (2) corticosterone (Cort) or vehicle injections, (3) CRS for 21 days and then a FST, or (4) allowed to recover 21 days after CRS and subjected to FST. Hippocampal mRNA was extracted and used to generate cDNA libraries for microarray hybridization. Naive acute stressors (FST and vehicle injection) altered similar sets of genes, but Cort treatment produced a profile that was distinct from both FST and vehicle. Exposure to a novel stress after CRS activated substantially more and different genes than naive exposure. Most genes increased by CRS were decreased after recovery but many remained altered and did not return to baseline. Pathway analysis identified significant clusters of differentially expressed genes across conditions, most notably the nuclear factor kappa-light-chain-enhancer of B cells (NF-κB) pathway. Quantitative reverse transcription-PCR (qRT-PCR) validated changes from the microarrays in known stress-induced genes and confirmed alterations in the NF-κB pathway genes, Nfkbia, RelA and Nfkb1. FST increased anxiety-like behavior in both the naive and recovery from CRS conditions, but not in mice 24h subsequent to their CRS exposure. These findings suggest that the effects of naive stress are distinct from Cort elevation, and that a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor. These findings establish a baseline profile of normal recovery and adaptation to stress. Importantly, they will serve as a conceptual basis to facilitate the future study of the cellular and regional basis of gene expression changes that lead to impaired recovery from stress, such as those that occur in mood and anxiety disorders.

Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition.

Converging evidence suggests that females and males show different responses to stress; however, little is known about the mechanism underlying the sexually dimorphic effects of stress. In this study, we found that young female rats exposed to 1 week of repeated restraint stress show no negative effects on temporal order recognition memory (TORM), a cognitive process controlled by the prefrontal cortex (PFC), which was contrary to the impairment in TORM observed in stressed males. Concomitantly, normal glutamatergic transmission and glutamate receptor surface expression in PFC pyramidal neurons were found in repeatedly stressed females, in contrast to the significant reduction seen in stressed males. The detrimental effects of repeated stress on TORM and glutamate receptors were unmasked in stressed females when estrogen receptors were inhibited or knocked down in PFC, and were prevented in stressed males with the administration of estradiol. Blocking aromatase, the enzyme for the biosynthesis of estrogen, revealed the stress-induced glutamatergic deficits and memory impairment in females, and the level of aromatase was significantly higher in the PFC of females than in males. These results suggest that estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and PFC-dependent cognition, which may underlie the stress resilience of females.

CB1 receptor signaling regulates social anxiety and memory.

The endocannabinoid (eCB) system regulates emotion, stress, memory and cognition through the cannabinoid type 1 (CB1 ) receptor. To test the role of CB1 signaling in social anxiety and memory, we utilized a genetic knockout (KO) and a pharmacological approach. Specifically, we assessed the effects of a constitutive KO of CB1 receptors (CB1 KOs) and systemic administration of a CB1 antagonist (AM251; 5 mg/kg) on social anxiety in a social investigation paradigm and social memory in a social discrimination test. Results showed that when compared with wild-type (WT) and vehicle-treated animals, CB1 KOs and WT animals that received an acute dose of AM251 displayed anxiety-like behaviors toward a novel male conspecific. When compared with WT animals, KOs showed both active and passive defensive coping behaviors, i.e. elevated avoidance, freezing and risk-assessment behaviors, all consistent with an anxiety-like profile. Animals that received acute doses of AM251 also showed an anxiety-like profile when compared with vehicle-treated animals, yet did not show an active coping strategy, i.e. changes in risk-assessment behaviors. In the social discrimination test, CB1 KOs and animals that received the CB1 antagonist showed enhanced levels of social memory relative to their respective controls. These results clearly implicate CB1 receptors in the regulation of social anxiety, memory and arousal. The elevated arousal/anxiety resulting from either total CB1 deletion or an acute CB1 blockade may promote enhanced social discrimination/memory. These findings may emphasize the role of the eCB system in anxiety and memory to affect social behavior.

Lithium's role in neural plasticity and its implications for mood disorders.

OBJECTIVE: Lithium (Li) is often an effective treatment for mood disorders, especially bipolar disorder (BPD), and can mitigate the effects of stress on the brain by modulating several pathways to facilitate neural plasticity. This review seeks to summarize what is known about the molecular mechanisms underlying Li's actions in the brain in response to stress, particularly how Li is able to facilitate plasticity through regulation of the glutamate system and cytoskeletal components. METHOD: The authors conducted an extensive search of the published literature using several search terms, including Li, plasticity, and stress. Relevant articles were retrieved, and their bibliographies consulted to expand the number of articles reviewed. The most relevant articles from both the clinical and preclinical literature were examined in detail. RESULTS: Chronic stress results in morphological and functional remodeling in specific brain regions where structural differences have been associated with mood disorders, such as BPD. Li has been shown to block stress-induced changes and facilitate neural plasticity. The onset of mood disorders may reflect an inability of the brain to properly respond after stress, where changes in certain regions may become 'locked in' when plasticity is lost. Li can enhance plasticity through several molecular mechanisms, which have been characterized in animal models. Further, the expanding number of clinical imaging studies has provided evidence that these mechanisms may be at work in the human brain. CONCLUSION: This work supports the hypothesis that Li is able to improve clinical symptoms by facilitating neural plasticity and thereby helps to 'unlock' the brain from its maladaptive state in patients with mood disorders.

Dynamic plasticity: the role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors.

Brain-derived neurotrophic factor (BDNF) is a secreted protein that has been linked to numerous aspects of plasticity in the central nervous system (CNS). Stress-induced remodeling of the hippocampus, prefrontal cortex and amygdala is coincident with changes in the levels of BDNF, which has been shown to act as a trophic factor facilitating the survival of existing and newly born neurons. Initially, hippocampal atrophy after chronic stress was associated with reduced BDNF, leading to the hypothesis that stress-related learning deficits resulted from suppressed hippocampal neurogenesis. However, recent evidence suggests that BDNF also plays a rapid and essential role in regulating synaptic plasticity, providing another mechanism through which BDNF can modulate learning and memory after a stressful event. Numerous reports have shown BDNF levels are highly dynamic in response to stress, and not only vary across brain regions but also fluctuate rapidly, both immediately after a stressor and over the course of a chronic stress paradigm. Yet, BDNF alone is not sufficient to effect many of the changes observed after stress. Glucocorticoids and other molecules have been shown to act in conjunction with BDNF to facilitate both the morphological and molecular changes that occur, particularly changes in spine density and gene expression. This review briefly summarizes the evidence supporting BDNF's role as a trophic factor modulating neuronal survival, and will primarily focus on the interactions between BDNF and other systems within the brain to facilitate synaptic plasticity. This growing body of evidence suggests a more nuanced role for BDNF in stress-related learning and memory, where it acts primarily as a facilitator of plasticity and is dependent upon the coactivation of glucocorticoids and other factors as the determinants of the final cellular response.

Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure.

Hyperactivation of the amygdala following chronic stress is believed to be one of the primary mechanisms underlying the increased propensity for anxiety-like behaviors and pathological states; however, the mechanisms by which chronic stress modulates amygdalar function are not well characterized. The aim of the current study was to determine the extent to which the endocannabinoid (eCB) system, which is known to regulate emotional behavior and neuroplasticity, contributes to changes in amygdalar structure and function following chronic stress. To examine the hypothesis, we have exposed C57/Bl6 mice to chronic restraint stress, which results in an increase in fatty acid amide hydrolase (FAAH) activity and a reduction in the concentration of the eCB N-arachidonylethanolamine (AEA) within the amygdala. Chronic restraint stress also increased dendritic arborization, complexity and spine density of pyramidal neurons in the basolateral nucleus of the amygdala (BLA) and increased anxiety-like behavior in wild-type mice. All of the stress-induced changes in amygdalar structure and function were absent in mice deficient in FAAH. Further, the anti-anxiety effect of FAAH deletion was recapitulated in rats treated orally with a novel pharmacological inhibitor of FAAH, JNJ5003 (50 mg per kg per day), during exposure to chronic stress. These studies suggest that FAAH is required for chronic stress to induce hyperactivity and structural remodeling of the amygdala. Collectively, these studies indicate that FAAH-mediated decreases in AEA occur following chronic stress and that this loss of AEA signaling is functionally relevant to the effects of chronic stress. These data support the hypothesis that inhibition of FAAH has therapeutic potential in the treatment of anxiety disorders, possibly by maintaining normal amygdalar function in the face of chronic stress.

Chronic, noninvasive glucocorticoid administration suppresses limbic endocannabinoid signaling in mice.

Limbic endocannabinoid signaling is known to be sensitive to chronic stress; however, studies investigating the impact of prolonged exposure to glucocorticoid hormones have been limited by the concurrent exposure to the stress of daily injections. The present study was designed to examine the effects of a noninvasive approach to alter plasma corticosterone (CORT) on the endocannabinoid system. More precisely, we explored the effects of a 4-week exposure to CORT dissolved in the drinking water of mice (100 µg/ml) and measured cannabinoid CB(1) receptor binding, endocannabinoid content, activity of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH), and mRNA expression of both the CB(1) receptor and FAAH in both the hippocampus and amygdala. Our data demonstrate that CORT decreases CB(1) receptor binding site density in both the hippocampus and amygdala and also reduced anandamide (AEA) content and increased FAAH activity within both structures. These changes in both CB(1) receptor binding and FAAH activity were not accompanied by changes in mRNA expression of either the CB(1) receptor or FAAH in either brain region. Interestingly, our CORT delivery regimen significantly increased 2-AG concentrations within the hippocampus, but not the amygdala. Collectively, these data demonstrate that the confounder of injection stress is sufficient to conceal the ability of protracted exposure to glucocorticoids to reduce CB(1) receptor density and augment AEA metabolism within limbic structures.

Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation.

Estradiol affects hippocampal-dependent spatial memory and underlying structural and electrical synaptic plasticity in female mice and rats. Using estrogen receptor (ER) alpha and beta knockout mice and wild-type littermates, we investigated the role of ERs in estradiol effects on multiple pathways important for hippocampal plasticity and learning. Six hours of estradiol administration increased immunoreactivity for phosphorylated Akt throughout the hippocampal formation, whereas 48 h of estradiol increased immunoreactivity for phosphorylated TrkB receptor. Estradiol effects on phosphorylated Akt and TrkB immunoreactivities were abolished in ER alpha and ER beta knockout mice. Estradiol also had distinct effects on immunoreactivity for post-synaptic density 95 (PSD-95) and brain derived-neurotrophic factor (BDNF) mRNA in ER alpha and beta knockout mice. Thus, estradiol acts through both ERs alpha and beta in several subregions of the hippocampal formation. The different effects of estradiol at 6 and 48 h indicate that several mechanisms of estrogen receptor signaling contribute to this female hormone's influence on hippocampal synaptic plasticity. By further delineating these mechanisms, we will better understand and predict the effects of endogenous and exogenous ovarian steroids on mood, cognition, and other hippocampal-dependent behaviors.

Specific regulatory motifs predict glucocorticoid responsiveness of hippocampal gene expression.

The glucocorticoid receptor (GR) is an ubiquitously expressed ligand-activated transcription factor that mediates effects of cortisol in relation to adaptation to stress. In the brain, GR affects the hippocampus to modulate memory processes through direct binding to glucocorticoid response elements (GREs) in the DNA. However, its effects are to a high degree cell specific, and its target genes in different cell types as well as the mechanisms conferring this specificity are largely unknown. To gain insight in hippocampal GR signaling, we characterized to which GRE GR binds in the rat hippocampus. Using a position-specific scoring matrix, we identified evolutionary-conserved putative GREs from a microarray based set of hippocampal target genes. Using chromatin immunoprecipitation, we were able to confirm GR binding to 15 out of a selection of 32 predicted sites (47%). The majority of these 15 GREs are previously undescribed and thus represent novel GREs that bind GR and therefore may be functional in the rat hippocampus. GRE nucleotide composition was not predictive for binding of GR to a GRE. A search for conserved flanking sequences that may predict GR-GRE interaction resulted in the identification of GC-box associated motifs, such as Myc-associated zinc finger protein 1, within 2 kb of GREs with GR binding in the hippocampus. This enrichment was not present around nonbinding GRE sequences nor around proven GR-binding sites from a mesenchymal stem-like cell dataset that we analyzed. GC-binding transcription factors therefore may be unique partners for DNA-bound GR and may in part explain cell-specific transcriptional regulation by glucocorticoids in the context of the hippocampus.

Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory.

Corticosteroid stress hormones have a strong impact on the function of prefrontal cortex (PFC), a central region controlling cognition and emotion, though the underlying mechanisms are elusive. We found that behavioral stressor or short-term corticosterone treatment in vitro induces a delayed and sustained potentiation of the synaptic response and surface expression of N-methyl-D-aspartic acid receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in PFC pyramidal neurons through a mechanism depending on the induction of serum- and glucocorticoid-inducible kinase (SGK) and the activation of Rab4, which mediates receptor recycling between early endosomes and the plasma membrane. Working memory, a key function relying on glutamatergic transmission in PFC, is enhanced in acutely stressed animals through an SGK-dependent mechanism. These results suggest that acute stress, by activating glucocorticoid receptors, increases the trafficking and function of NMDARs and AMPARs through SGK/Rab4 signaling, which leads to the potentiated synaptic transmission, thereby facilitating cognitive processes mediated by the PFC.

Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons.

Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF(±) ) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF(±) mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF(±) mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling.

The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation.

Tianeptine is a clinically used antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It is now acknowledged that the antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key function of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. This article reviews the latest evidence on tianeptine's mechanism of action with a focus on the glutamatergic system, which could provide a key pathway for its antidepressant action. Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.