Nature Neuroscience - Focus on emotion and disorders of emotion

Emotion and Disorder of Emotion

Nature Neuroscience - 10, 1089 - 1093 (2007)

Published online: 28 August 2007; | doi:10.1038/nn1971

New insights into BDNF function in depression and anxiety

Keri Martinowich1, Husseini Manji1 & Bai Lu2

1 Mood and Anxiety Program, National Institute of Mental Health, Building 35, Room 1C1004, 35 Convent Drive, MSC 3714, Bethesda, Maryland 20892-3714, USA.

2 Section on Neural Development & Plasticity, National Institute of Child Health and Human Development; National Institutes of Health, Building 35, Room 1C1004, 35 Convent Drive, MSC 3714, Bethesda, Maryland 20892-3714, USA. Этот e-mail адрес защищен от спам-ботов, для его просмотра у Вас должен быть включен Javascript

Abstract

The 'neurotrophin hypothesis of depression' is based largely on correlations between stress or antidepressant treatment and down- or upregulation, respectively, of brain-derived neurotrophic factor (BDNF). Genetic disruption of the signaling pathways involving BDNF and its receptor, the tyrosine kinase TrkB, does not seem to cause depressive behaviors, but does hamper the effect of antidepressant drugs. Thus, BDNF may be a target of antidepressants, but not the sole mediator of depression or anxiety. Advances in BDNF cell biology, including its transcription through multiple promoters, trafficking and secretion, may provide new insights into its role in mood disorders. Moreover, as the precursor proBDNF and the mature protein mBDNF can elicit opposite effects on cellular functions, the impact of proBDNF and its cleavage on mood should be considered. Opposing influences of mBDNF and proBDNF on long-term potentiation and long-term depression might contribute to the dichotomy of BDNF actions on behaviors mediated by the brain stress and reward systems.

Main paper

Mood and anxiety disorders are among the most disabling of all medical disorders. They frequently appear early in life, run a chronic course and adversely affect the prognosis of other medical illnesses1. Understanding the cellular and molecular bases of these disorders is crucial in the effort to effect new treatments. BDNF, a secretory protein in the neurotrophin family, has been implicated in both depression and anxiety. The 'neurotrophin hypothesis of depression' is based largely on observations that decreases in hippocampal BDNF levels are correlated with stress-induced depressive behaviors and that antidepressant treatment enhances the expression of Bdnf2. Despite extensive studies over the past decade, a number of key questions remain to be fully addressed. Does BDNF dysfunction lead to depression? Are antidepressant effects mediated by BDNF, and, if so, which facets of the overall antidepressant response (for example, mood, motivation, cognition) are affected? Recent progress in understanding the cell biology of BDNF may provide new avenues examining its role in mood disorders. For example, multiple promoters drive Bdnf transcription, and antidepressants seem to act selectively at some promoters, but not others3, 4, 5. Such findings encourage a more mechanistic delineation of potential causal relationships between BDNF and discrete aspects of these complex illnesses. Future studies will benefit from separating BDNF's role in mediating depressive and anxiety behaviors from those involved in antidepressant drug action. Moreover, emerging evidence indicates that BDNF may have different and perhaps opposing roles in the brain stress system, including the hippocampus and hypothalamus-pituitary-adrenocortical (HPA) axis, and in the brain reward system, including the nucleus accumbens (NAc) and the ventral tegmental area (VTA)6, 7. Finally, BDNF is first synthesized as a precursor proBDNF, which is proteolytically cleaved to generate mature BDNF (mBDNF). Recent studies have demonstrated that proBDNF and mBDNF facilitate long-term depression (LTD) and long-term potentiation (LTP), respectively, implying opposing cellular functions8, 9, 10. Thus, it is important to determine whether depressive and anxiety-like behaviors or antidepressant effects are mediated by signaling through proBDNF or through mBDNF. We discuss how these new findings affect our understanding of BDNF in mood disorders.

Stress, antidepressants and BDNF

As stressful life events have a substantial causal association with depression and anxiety1, 11, stress paradigms have long been used to model these diseases. Notably, it has been shown that stress can lead to neuronal atrophy and loss in several brain regions, including the hippocampus2, 11. Numerous studies have also documented that stress decreases the expression of Bdnf mRNA in the hippocampus2, 12. Conversely, many classes of chemical antidepressants, as well as electroconvulsive shock treatment, can significantly increase Bdnf mRNA expression in the hippocampus, prefrontal cortex or both2, 4, 13. This increase depends on chronic antidepressant treatment13, which is consistent with the slow onset of therapeutic effects of antidepressants in a clinical setting. Furthermore, limited studies have shown that direct hippocampal infusions of BDNF protein can produce antidepressant effects in rodents14, 15. These studies support the 'neurotrophin hypothesis of depression', which postulates that reduced brain levels of BDNF could contribute to atrophy and cell loss in the hippocampus and prefrontal cortex, as observed in depressed subjects, whereas antidepressants may exert their therapeutic effects by increasing BDNF expression, thereby leading to the reversal of neuronal atrophy and cell loss2. Although undoubtedly heuristic, the hypothesis has yet to provide mechanistic insights into how increases or decreases in BDNF could cause an antidepressant or depressive effect.

Few human studies have attempted to address this hypothesis, but the extant data do provide some correlative support. Thus, compared with normal human subjects, levels of BDNF are lower in postmortem brain tissue from depressed patients but higher in those who were taking antidepressants at the time of death16. Furthermore, brain imaging studies have documented a reduction in hippocampal volume in depressed subjects17, which can be attenuated by antidepressant treatment17. In light of these and other clinical findings, studies have attempted to identify single-nucleotide polymorphisms (SNPs) in Bdnf that may underlie its dysfunction in mood disorders. A SNP was identified in the region encoding BDNF's pro-domain leading to a valine at amino acid 66 being substituted with a methionine (Val66Met). Association studies with this polymorphism have been variable, but most analyses have suggested that the Met allele is protective for bipolar disorder18, 19. Although existing studies suggested that stress and antidepressants have opposite effects on hippocampal Bdnf expression, they have only correlated changes in total levels of Bdnf mRNA or BDNF protein. Therefore, it remains unclear which Bdnf transcript(s), or whether proBDNF or mBDNF, is functioning to mediate a depressive or antidepressant response.

Because stress decreases other neurotrophic factors and because electroconvulsive shock treatment and antidepressants induce the expression of other growth factors2, attempts to validate BDNF as having a central role in the pathophysiology and treatment of depression have been complicated. As we move forward, it is imperative to recognize that in the adult brain, BDNF is primarily involved in synaptic plasticity, as opposed to cell survival or dendritic growth. In this context, it is noteworthy that recent clinical studies suggest that NMDA antagonists may produce robust antidepressant effects within two hours20, which are likely to be mediated by changes in synaptic plasticity rather than in dendritic growth.

BDNF cell biology and mood disorders

Considerable progress has been made in our understanding of the mechanisms underlying the transcription, trafficking and secretion and processing of BDNF. These new findings may have a significant impact on our understanding of BDNF's role in the pathophysiology and treatment of mood disorders. Readers may find more detailed discussions of current advances in BDNF cell biology elsewhere8, 21.

Transcription. Bdnf has an extremely complex genomic structure. There are at least four promoters, each of which drives a short 5' untranslated 'exon' that is alternatively spliced to a common 3' coding exon encoding the BDNF protein22. Recent studies have revealed as many as seven promoters in the Bdnf gene23, but here we use a relatively old nomenclature based on the initial characterization of four promoters in the rat22, 24. Cumulative evidence indicates that these transcripts are differentially distributed across different brain regions, in different cell types and even within different parts of the neuron. For example, exon III transcripts are detected only in cell bodies, whereas exon IV transcripts are present in cell bodies and dendritic processes of visual cortex neurons25. These promoters are differentially activated in response to diverse and varied signaling events. Interestingly, different antidepressants enhance Bdnf expression using different combinations of promoters3, 4, 5. Transcription through promoter III has been well studied because it is highly responsive to neuronal activity and is therefore implicated in synapse development as well as learning and memory24.

Remarkably, promoter III is a target of epigenetic regulation26, 27. Promoter III transcription is suppressed by MeCP2, a transcriptional repressor that binds methylated DNA. Neuronal depolarization leads to the release of MeCP2 along with its repression complex partners, HDAC1 and Sin3a26, 27. Furthermore, chronic social defeat stress in mice (used as a model to induce depressive-like behaviors) produces long-lasting suppression of Bdnf transcripts III and IV in the hippocampus by means of an increase in dimethylation of histone 3 (H3) on the chromatin of the respective promoters. H3 dimethylation is associated with chromatin compaction and can lead to an enduring repressive state, which is associated with lower levels of Bdnf transcription5. Interestingly, chronic treatment with the antidepressant imipramine counteracts the reduction in exon III transcription by inducing acetylation of H3, which is associated with a more euchromatic state5. These results draw attention to the possible role of chromatin remodeling and epigenetic regulation in the pathophysiology of mood disorders, an area largely unexplored until recently. As social defeat behaviors have also been correlated with changes in Bdnf gene expression in the VTA6, it will be interesting to determine whether epigenetic alterations at the Bdnf promoter III underlie these changes as well. A key unresolved question is whether upregulation of Bdnf through promoter III is a main target for the therapeutic actions of antidepressants. Mouse models with promoter-specific mutations may help to address this question.

Trafficking, secretion and cleavage. All Bdnf transcripts are translated in the endoplasmic reticulum into proBDNF, which is then folded in the trans-Golgi and packaged into secretory vesicles where it can be sorted into either the constitutive (spontaneous release) or, more frequently, the regulated (release in response to stimuli) secretory pathway28. BDNF-containing vesicles are trafficked to neuronal dendrites and spines, as well as to axons and terminals. Dendritic trafficking and synaptic localization are controlled by BDNF's pro-domain, particularly in the region encompassing the Val66Met SNP ('box2/3')29, 30. Notably, this region has a key role in activity-dependent BDNF secretion29, 30. Biochemical and imaging experiments have demonstrated that box2/3 interacts with sortilin, a newly identified neurotrophin receptor. The BDNF-sortilin interaction is markedly reduced by the presence of the Val66Met allele. Inhibition of this interaction by expressing either a truncated sortilin lacking its transmembrane domain, box2/3 peptide or Val66Met BDNF attenuates dendritic trafficking as well as depolarization-induced secretion of BDNF30. In a mouse knock-in model carrying the Val66Met polymorphism, activity-dependent secretion of BDNF is significantly reduced, whereas total levels of BDNF as well as its constitutive secretion are not changed31. Remarkably, these mice show increased anxiety-related behaviors that cannot be normalized by antidepressants. These results demonstrate the importance of dendritic trafficking, regulated BDNF secretion or both and indicate that BDNF may be a mediator of the anxiolytic effect of antidepressants31. Notably, hippocampal volume in the BdnfMet/Met mice is reduced; whether these animals also show depressive behaviors remains to be investigated. In a larger context, activity-dependent secretion, a feature unique to BDNF and not seen with other neurotrophins or growth factors, may be one of the key elements in mood regulation. This may explain why BDNF is more likely than other neurotrophins to be involved in mood disorders.

A large proportion of neuronal BDNF is secreted in the pro-form, which is subsequently converted to mBDNF by extracellular proteases such as plasmin or matrix metalloproteinases32 (G. Nagappan and B.L., unpublished data). Of particular interest is tissue plasminogen activator (tPA), an extracellular protease that converts the inactive zymogen plasminogen to plasmin. It has been shown that tPA, through activation of plasmin, converts proBDNF to mBDNF in the hippocampus and that this conversion is required for late phase LTP9. Thus, the tPA-plasmin system is critical in controlling the availability of mBDNF at hippocampal synapses. Recent studies have also implicated p11 (annexin II light chain), a membrane-associated protein known to dramatically enhance tPA activity33, in the pathogenesis of depression34. Antidepressant treatment leads to p11 upregulation, whereas transgenics overexpressing p11 behave similarly to antidepressant-treated animals34. Conversely, mice lacking p11 show depressive-like behaviors. Svenningsson et al. attributed the antidepressant function of p11 to its ability to interact with and facilitate the cell surface expression of the serotonin 5-HT1B receptor. However, in light of p11's ability to enhance tPA function, it may be possible that the effect of p11 dysfunction on depressive behaviors is a result of a reduction in proBDNF cleavage.

ProBDNF, p75NTR and the yin-yang hypothesis. All neurotrophins arise from precursors, proneurotrophins, which are proteolytically cleaved to produce mature proteins. Proneurotrophins were previously considered predominantly inactive and their existence in vivo has been debated. Using antibodies specific for proBDNF, recent studies have clearly shown that proBDNF is widely and abundantly expressed throughout the adult brain35 (G. Nagappan, K.M. and B.L., unpublished data). The idea that proneurotrophins were functionally inactive was challenged by the demonstration that they bind preferentially to the pan-neurotrophin receptor p75NTR, as opposed to the Trk receptor tyrosine kinases, and elicit apoptosis rather than cell survival in some peripheral neurons. Recent studies have extended the reciprocal effects of pro- versus mature neurotrophins in survival versus apoptosis to the CNS by showing that cholinergic neurons in the basal forebrain are susceptible to detrimental effects of proneurotrophins, whereas their survival is promoted by mature neurotrophins36. Cleaved, mature neurotrophins bind their cognate Trk receptors, leading to a cascade of intracellular signaling promoting cell survival. These findings have led to the 'yin-yang hypothesis': pro- and mature neurotrophins elicit opposite biological actions through binding to p75NTR and Trk receptors, respectively8. This hypothesis can be extended beyond cell survival to synaptic plasticity in the hippocampus8. There, activation of TrkB has a critical role in early phase LTP37. In addition, conversion of proBDNF to mBDNF by the tPA-plasmin system is required for TrkB-mediated late-phase LTP9. In contrast, proBDNF facilitates LTD via activation of p75NTR (ref. 10). Activation of TrkB and p75NTR promotes and suppresses dendritic spine growth, respectively38. Cleavage of proBDNF may therefore represent a new mechanism that controls the direction of BDNF regulation: synaptic potentiation or synaptic depression.

The yin-yang hypothesis provides a new perspective on the neurotrophin hypothesis of depression and could, in theory, help to interpret some of the conflicting results obtained in relation to BDNF signaling in mood disorders. For example, most animal models with reduced BDNF signaling or a deleted Bdnf gene do not show a clear depressive-like phenotype39, 40. If proBDNF and mBDNF act in opposite directions in 'depressive behaviors', deletion of the Bdnf gene would remove both positive and negative signals, counteracting any observable behavior. Notably, transgenic mice overexpressing the Bdnf gene in the forebrain show both anxiogenic and antidepressant effects41. Elevated levels of both proBDNF and mBDNF could offer an explanation for these two seemingly opposing behavioral phenotypes. Even more puzzling is the behavior of tPA and plasminogen mutant mice. Both lines show higher levels of proBDNF (and lower levels of mBDNF), particularly in the hippocampus9. Notably, acute stress does not activate MAP kinase, a key signaling event downstream of mBDNF-TrkB, in mice lacking tPA. Moreover, these mice show no anxiogenic behaviors after repeated restraint stress42. However, if impairment in proBDNF cleavage underlies these behaviors, it remains unclear whether these effects result from a reduction in mBDNF levels or an accumulation of proBDNF. Transgenic mice overexpressing a cleavage-resistant form of proBDNF may help to separate the distinct roles of proBDNF and mBDNF in mood behaviors. In addition, methods that can effectively detect proBDNF and mBDNF with high sensitivity and specificity are crucial in discerning the yin and yang actions of BDNF in its potential depressive and antidepressant effects. Finally, studying the function of p75NTR in adult animals under various stress or depression conditions may provide new insight. Whereas p75NTR is expressed highly and widely during development, its expression in the adult brain is restricted mainly to the cholinergic neurons of the basal forebrain. These neurons innervate many brain areas, including the hippocampus, prefrontal cortex, amygdala and nucleus accumbens, all of which have been implicated in mood and stress-related behaviors. Moreover, it has been shown that whereas hippocampal expression of p75NTR is very low in basal states, it is dramatically upregulated after seizure or injury43. Thus, it is possible that p75NTR expression could be elevated after behavioral stress or during depression. Interestingly, stress also enhances the expression of sortilin, a coreceptor for proBDNF44. While the yin-yang hypothesis does not mean that the two signaling systems carry the same weight, the emerging concept of proBDNF-p75NTR signaling opens up an exciting new avenue in the study of mood disorders.

New insights into puzzling experimental data

BDNF's role in depression and anxiety versus in antidepressant action. As compelling as the correlation between BDNF expression and depression seems, a key gap in the neurotrophin hypothesis is the paucity of direct evidence that inhibition of BDNF signaling leads to depressive-like behaviors39, 40. One report showed that Bdnf+/- mice show slower escape latencies in the learned helplessness paradigm, but this result could be attributed to an impaired shock response39. Although two recent studies found some evidence for depressive-like behaviors in mice lacking BDNF in the forebrain, the effects were small and inconsistent (deficits in tail suspension but not forced swim test or in females but not in males)45. Moreover, mice lacking TrkB in the forebrain as well as transgenics overexpressing the dominant-negative T1 form of TrkB show no impairment in depressive-like behaviors40, 46. Overall, these results question whether impairment in BDNF-TrkB signaling is a principal cause of depression. In contrast, in both BDNF knockouts and TrkB-T1 transgenic mice, antidepressant treatment is no longer effective in reducing immobility in the forced swim test (FST), indicating that BDNF-TrkB signaling is somehow necessary for the positive effect on behavioral despair40. Interestingly, acute treatment is sufficient to exert effects on the FST, whereas chronic (21 days) administration is required to induce the expression of Bdnf and Ntrk2 mRNAs in wild-type mice13. Thus, the effect of antidepressants on FST is likely to be mediated by an acute increase in BDNF secretion, TrkB signaling or both40, rather than by an enhancement of expression of either gene. It will be critical to determine the behavioral effects of chronic treatment with antidepressants in BDNF and TrkB mutant mice. Regardless of their time courses, these data raise the interesting possibility that antidepressants elicit their effects by activating the BDNF-TrkB pathway.

The incongruent findings regarding the role of BDNF in depression and that in antidepressant effects indicate the need to separate these two seemingly related phenomena. Clinical depression may not be triggered by deficits in BDNF signaling alone but, rather, may require impairments in multiple pathways. Alternatively, downregulation of BDNF-TrkB could be compensated by upregulation of other neurotrophic or growth factors. It is also possible that both genetic factors and stressors may contribute to the development of depression through mechanisms completely independent of BDNF and that antidepressants, through activation of BDNF-TrkB signaling, may interfere with these mechanisms to attenuate depressive behaviors.

Antidepressants are also used to treat a variety of anxiety disorders. Both BdnfMet/Met and Bdnf+/- mice show increased anxiety-related behaviors31. Treatment with the antidepressant fluoxetine was unable to reverse behavioral anxiety in either Bdnf+/- or BdnfMet/Met mice, indicating that BDNF may be a downstream target of selective serotonin reuptake inhibitors31, a class of antidepressants. Consistent with this, the Bdnf+/-; and serotonin transporter Slc6a4+/- (also known as SERT+/-) double mutant shows a more pronounced anxiogenic phenotype as compared with singly heterozygous mice47. These results imply that the antidepressant effect of selective serotonin reuptake inhibitors on anxiety is mediated by the BDNF-TrkB signaling.

Although depression and anxiety are often comorbid, they do retain separate etiologies. It is therefore important to examine the specific role of BDNF in depression and anxiety. However, behavioral assays available at present often cannot effectively separate depressive from anxiety-like behaviors and are at best a partial reflection of certain aspects of the human disease etiology. Thus, we must exercise caution in interpreting behavior data and their relevance to these behaviors in humans. Nevertheless, converging evidence indicates that the BDNF-TrkB signaling may be a main target of antidepressants but that inhibition of this pathway may not be a main cause of depression.

Differential effects on the brain stress and reward systems. Depression is characterized by 'behavioral despair' as well as by the inability to experience pleasure (anhedonia). These two sets of behaviors are likely to be controlled by two distinct, albeit interacting, brain systems: the brain stress system (hippocampus-HPA pathway) and the brain reward system (VTA-NAc and VTA–prefrontal cortex pathways). The hippocampal circuitry includes functional components for learning and memory as well as negative regulation of the HPA-mediated stress pathway, both of which are altered in depression. The dopaminergic VTA right arrow NAc pathway has a crucial role in reward and motivation. It seems that BDNF elicits opposite effects on these two systems. Intrahippocampal infusion of BDNF produces antidepressant effects14, 15, whereas, in marked contrast, it seems to have a pro-depressive role in the VTA right arrow NAc reward system7. Conversely, inhibition of BDNF-TrkB signaling by viral infection of dominant-negative TrkB-T1 in NAc, the target of VTA dopaminergic neurons, elicits a strong antidepressive effect7. Using a social defeat paradigm, Berton et al. recently showed that repeated exposure to aggression results in long-lasting social withdrawal in mice6. Selective deletion of the Bdnf gene in the NAc through injection of a Cre-recombinase virus in mice carrying a loxP-flanked ('floxed') Bdnf allele prevents social defeat, mirroring the effect obtained with chronic antidepressant treatment6.

The clear dichotomy of BDNF actions in the hippocampus and VTA-NAc demands separate investigation of the effects of BDNF manipulations on behaviors related to (i) anhedonia and motivation and (ii) despair and stress. Inducible and region-specific genetic approaches, which are more precise and cell-type specific, will be advantageous. As the NAc is largely composed of GABAergic interneurons, which presumably do not express BDNF, local BDNF may be primarily derived from glia. Differences in the kinetics of Bdnf transcription or BDNF secretion in neurons and glia may lead to contrasting effects in the hippocampus and NAc. It will also be interesting to determine how efficiently proBDNF in the NAc is processed to mBDNF. Infusion of high doses of BDNF, as was the case in the study by Eisch and colleagues7, could activate p75NTR, whereas deletion of the Bdnf gene in the NAc, as was the case in the study by Berton and colleagues6, deletes both proBDNF and mBDNF. Thus, we could hypothesize a pro-depressive role by proBDNF in the VTA-NAc system. Whereas the antidepressant effects on behavior despair are mediated by mBDNF-TrkB signaling in the hippocampus, it is tempting to speculate that proBDNF-p75NTR mechanisms are involved in the VTA-NAc–mediated anhedonic phenotype. Selective deletion of genes encoding receptors (p75NTR or TrkB) in the hippocampus or NAc may prove helpful in delineating the specific role of proBDNF and mBDNF in depressive behaviors.

Does proBDNF-p75 regulation of LTD contribute to depression? Initially, the neurotrophin hypothesis focused on the growth and survival effect of neurotrophins2. However, it has become increasingly clear that the main function of BDNF in the adult brain is to regulate synaptic plasticity, rather than to mediate neuronal morphology or viability. Mature BDNF is now widely recognized as a key regulator of LTP in the hippocampus8. In general, various forms of stress impair LTP, and antidepressants reverse that effect. It is conceivable that antidepressants promote mBDNF-TrkB signaling and expression, leading to an enhancement of hippocampal LTP. The role of proBDNF-p75NTR in depression and antidepressant effects has not yet been examined.

However, emerging evidence supports the idea that LTD may have a role in depressive-like behaviors. Acute stress can induce LTD in the adult hippocampus, which normally does not show LTD48. Recent studies reported a correlation between behavioral stress and the induction of LTD in adult rats49. Moreover, chronic mild stress–induced LTD could be reversed by chronic treatment with an antidepressant49. However, it is unclear whether LTD is the cause or the consequence of depression in this scenario. Interestingly, activation of p75NTR by proBDNF also selectively facilitates, whereas inhibition of p75NTR by gene knockout selectively impairs, NMDA receptor–dependent LTD, but not LTP, in the juvenile hippocampus10, 50. It is tempting to speculate that the LTD observed after the behavioral stress paradigms are proBDNF-p75NTR–dependent, such that behavioral stress might induce secretion of proBDNF, enhanced expression of p75NTR in the hippocampus or both. The proBDNF-p75NTR interaction leads to LTD and spine atrophy and, therefore, attenuates hippocampus-HPA control, leading to depressive-like behaviors. Critical tests of this model include examining whether selective blockade of proBDNF-p75NTR signaling or LTD can prevent stress-induced depression and whether selective elevation of proBDNF levels or enhancement of LTD can lead to depressive-like behaviors. Regardless of experimental outcomes, critically examining the role of synaptic plasticity in depression and anxiety may represent an exciting new direction in research for mood disorders.

Published online: 28 August 2007.

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Acknowledgments

The authors' work is supported by funds from intramural research programs of the US National Institute of Mental Health and National Institute of Child Health and Human Development.

Competing interests statement: The authors declare no competing financial interests.