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Route to fast antidepressants? Antidepressants such as selective serotonin re-uptake inhibitors can take months to take effect, but small doses of ketamine, a glutamatergic N-methyl-D-aspartate receptor (NMDAR) agonist, can have antidepressant effects within hours. The antidepressant mechanism of ketamine is not well understood. Work in mice shows that antidepressant-like effects of ketamine depend on rapid synthesis of brain-derived neurotrophic factor (BDNF). Ketamine-mediated NMDAR blockade deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and de-suppression of BDNF translation. These findings raise the possibility of this pathway as a therapeutic target for fast-acting antidepressants. Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR ( N -methyl- D -aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear 1 , 2 , 3 . Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks 1 , 2 , 3 , unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients 3 . The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.

Neurotrophic factors, a family of secreted proteins that support the growth, survival and differentiation of neurons, have been intensively studied for decades due to the powerful and diverse effects on neuronal physiology, as well as their therapeutic potential. Such efforts have led to a detailed understanding on the molecular mechanisms of neurotrophic factor signaling. One member, brain-derived neurotrophic factor (BDNF) has drawn much attention due to its pleiotropic roles in the central nervous system and implications in various brain disorders. In addition, recent advances linking the rapid-acting antidepressant, ketamine, to BDNF translation and BDNF-dependent signaling, has re-emphasized the importance of understanding the precise details of BDNF biology at the synapse. Although substantial knowledge related to the genetic, epigenetic, cell biological and biochemical aspects of BDNF biology has now been established, certain aspects related to the precise localization and release of BDNF at the synapse have remained obscure. A recent series of genetic and cell biological studies have shed light on the question—the site of BDNF release at the synapse. In this Perspectives article, these new insights will be placed in the context of previously unresolved issues related to BDNF biology, as well as how BDNF may function as a downstream mediator of newer pharmacological agents currently under investigation for treating psychiatric disorders.

Key Points Brain-derived neurotrophic factor (BDNF) is widely produced in the cortex throughout life, where it influences neuronal function. Levels of BDNF become deficient in the cerebral cortex in Alzheimer's disease. In animal models of Alzheimer's disease, BDNF exhibits potent therapeutic effects that include prevention of cell death, stimulation of neuronal function, improvement in synaptic markers and improvements in learning and memory. Accordingly, BDNF represents a potentially promising therapeutic avenue in Alzheimer's disease. Other neurological and psychiatric disorders — for example, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and depression — could also respond to BDNF treatment. Therapeutic BDNF delivery to the brain is a major challenge. BDNF does not readily cross the blood–brain barrier, and widespread central administration causes intolerable adverse effects. Localized and sustained delivery of the growth factor will be required to treat many neurological disorders. Gene therapy may be a useful method of delivering BDNF to specific brain regions in neurological disorders. For example, clinical trials involving BDNF gene delivery to the entorhinal and/or the hippocampal circuitry regions in Alzheimer's disease are planned. Other methods for increasing BDNF levels in the brain include the use of small peptide mimetics, drug-induced increases in BDNF and even exercise. It remains to be established, however, whether these methods can induce sufficient increases in BDNF levels to effectively treat neurological diseases. Brain-derived neurotrophic factor (BDNF), which acts through its receptor tropomyosin-related kinase receptor type B, has diverse effects on neuronal function and survival in the adult brain. Nagahara and Tuszynski review the potential therapeutic use of BDNF in the treatment of various disorders of the central nervous system, such as Alzheimer's disease, and discuss the challenges to effective delivery of BDNF and possible strategies to overcome them. The growth factor brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase receptor type B (TRKB) are actively produced and trafficked in multiple regions in the adult brain, where they influence neuronal activity, function and survival throughout life. The diverse presence and activity of BDNF suggests a potential role for this molecule in the pathogenesis and treatment of both neurological and psychiatric disorders. This article reviews the current understanding and future directions in BDNF-related research in the central nervous system, with an emphasis on the possible therapeutic application of BDNF in modifying fundamental processes underlying neural disease.

Key Points Scientific advancement in neuroscience has not been effectively translated into therapies for neurological diseases. In general, 'toxin reducing' approaches (for example, lowering amyloid-β (Aβ)) thus far have not resulted in halting or delaying disease progression. A paradigm shift in the discovery of disease-modifying therapies for neurological diseases is urgently needed. For neurodegenerative diseases, targeting the pathophysiology rather than the pathogenesis may be more effective to achieve therapeutic intervention. The toxin reducing approach may work if treatment starts very early on in the disease process. Synapse degeneration is a major pathophysiological feature that correlates with disease progression in multiple neurodegenerative diseases. Neuronal loss is irreversible, whereas synapses can be repaired and regenerated. Three aspects of synaptic physiology can be targeted: synaptic transmission, synaptic plasticity and synaptic growth. For disease-modifying therapy, synaptic plasticity and, more importantly, synaptic growth should be targeted. Brain-derived neurotrophic factor (BDNF) is an exemplar of synaptic repair therapy, as it regulates all three aspects of synaptic physiology. It protects and repairs existing synapses and stimulates new synapse formation, even in the presence of various toxins. In humans, the BDNF Val66Met polymorphism in conjunction with high Aβ deposits confers faster decline in Alzheimer's disease endophenotypes such as episodic memory and hippocampal volume, and therefore could be considered as a patient stratification strategy for clinical trials with enhanced sensitivity and robustness. Success of a 'synaptic repair' therapy depends on whether synaptic dysfunction and synaptic repair and/or regeneration can be measured in the clinic. Efforts should be made to develop sensitive and reliable methodologies to measure synaptic function in humans in vivo . Opportunities and challenges in developing BDNF–TRKB pathway-based therapies, including delivery, are discussed. A combination of synaptic therapy and a more reliable and sensitive method (or methods) to measure synaptic changes may pave the way for developing disease-modifying medicines for debilitating neurological diseases. This Review highlights recent discoveries, discusses emerging concepts and proposes synapse-based therapies for treating neurodegenerative diseases. Synaptic dysfunction is a key pathophysiological hallmark in several neurodegenerative disorders. In this Review, Lu and colleagues consider a 'synaptic repair'-based therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis and discuss BDNF as a potential synaptic repair molecule. Increasing evidence suggests that synaptic dysfunction is a key pathophysiological hallmark in neurodegenerative disorders, including Alzheimer's disease. Understanding the role of brain-derived neurotrophic factor (BDNF) in synaptic plasticity and synaptogenesis, the impact of the BDNF Val66Met polymorphism in Alzheimer's disease-relevant endophenotypes — including episodic memory and hippocampal volume — and the technological progress in measuring synaptic changes in humans all pave the way for a 'synaptic repair' therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis. This article reviews the key issues in translating BDNF biology into synaptic repair therapies.

Animal models point towards a key role of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in mediating exercise-induced structural and functional changes in the hippocampus. Recently, also platelet derived growth factor-C (PDGF-C) has been shown to promote blood vessel growth and neuronal survival. Moreover, reductions of these neurotrophic and angiogenic factors in old age have been related to hippocampal atrophy, decreased vascularization and cognitive decline. In a 3-month aerobic exercise study, forty healthy older humans (60 to 77years) were pseudo-randomly assigned to either an aerobic exercise group (indoor treadmill, n=21) or to a control group (indoor progressive-muscle relaxation/stretching, n=19). As reported recently, we found evidence for fitness-related perfusion changes of the aged human hippocampus that were closely linked to changes in episodic memory function. Here, we test whether peripheral levels of BDNF, IGF-I, VEGF or PDGF-C are related to changes in hippocampal blood flow, volume and memory performance. Growth factor levels were not significantly affected by exercise, and their changes were not related to changes in fitness or perfusion. However, changes in IGF-I levels were positively correlated with hippocampal volume changes (derived by manual volumetry and voxel-based morphometry) and late verbal recall performance, a relationship that seemed to be independent of fitness, perfusion or their changes over time. These preliminary findings link IGF-I levels to hippocampal volume changes and putatively hippocampus-dependent memory changes that seem to occur over time independently of exercise. We discuss methodological shortcomings of our study and potential differences in the temporal dynamics of how IGF-1, VEGF and BDNF may be affected by exercise and to what extent these differences may have led to the negative findings reported here. •Exercise-related changes in BDNF, IGF, VEGF and PDGF were measured in older adults•Changes in hippocampal perfusion, volume (via 7T MRI) and memory were assessed•Fitness-related vascular hippocampal plasticity was not linked to growth factors•Changes in IGF-I, hippocampal volume and memory were linked independent of exercise•Potential reasons for negative findings and methodological shortcomings are discussed

Key Points Brain-derived neurotrophic factor (BDNF) has an important role in the control of energy balance in addition to its roles in neuronal survival and development. Mutations in the gene encoding BDNF or its receptor tropomyosin receptor kinase B (TrkB) lead to marked overeating and severe obesity in both mice and humans. Nutritional state, glucose and anorexigenic hormones, such as leptin and melanocortin, have been found to regulate BDNF gene expression in some known appetite-regulating brain regions such as the ventromedial hypothalamus and dorsal vagal complex, indicating that BDNF actively participates in the control of satiety. It is likely that multiple brain regions mediate the effect of BDNF on energy balance. These brain regions include the arcuate nucleus of the hypothalamus, paraventricular hypothalamus, ventromedial hypothalamus and dorsal vagal complex. The paraventricular hypothalamus is a key structure that produces BDNF to control energy balance. BDNF neurons in the anterior part of this nucleus inhibit food intake and stimulate locomotor activity, whereas BDNF neurons in the medial and posterior parts of the nucleus drive adaptive thermogenesis by polysynaptically projecting to brown adipose tissues. Administration of recombinant ciliary neurotrophic factor (CNTF) can overcome leptin resistance to suppress the appetite and to induce lasting weight loss in obese rodents and humans. CNTF probably reduces obesity-related phenotypes by regulating gene expression in neurons of the arcuate nucleus and by stimulating adult neurogenesis in the hypothalamus. There is accumulating evidence that some neurotrophic factors, particularly brain-derived neurotrophic factor and ciliary neurotrophic factor, could have a role in preventing obesity. In this Review, Xu and Xie discuss the neural mechanisms by which these molecules regulate energy intake and expenditure. Energy balance — that is, the relationship between energy intake and energy expenditure — is regulated by a complex interplay of hormones, brain circuits and peripheral tissues. Leptin is an adipocyte-derived cytokine that suppresses appetite and increases energy expenditure. Ironically, obese individuals have high levels of plasma leptin and are resistant to leptin treatment. Neurotrophic factors, particularly ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF), are also important for the control of body weight. CNTF can overcome leptin resistance in order to reduce body weight, although CNTF and leptin activate similar signalling cascades. Mutations in the gene encoding BDNF lead to insatiable appetite and severe obesity.

The purpose of this study was to test if different intensities of aerobic exercise could influence abdominal fat, isoforms of BDNF and executive function. Twenty obese men (30.0 ± 5.4 years old; 34.4 ± 3.5 kg/m 2 ) were randomized to moderate-intensity continuous training (MICT, n = 10) and high-intensity intermittent training (HIIT, n = 10) three times a week for 6 weeks, with isoenergetic energetic expenditure for each exercise session (~ 300 kcal) between conditions. Abdominal fat was assessed pre- and post-intervention; executive function (Coding subtest from BETA-III non-verbal intelligence test and Stroop Color and Word Test), concentrations of mBDNF and proBDNF were assessed in response to acute exercise pre- and post-intervention. Abdominal fat did not change in either group. There was a significant increase in mBDNF immediately after acute exercise in both groups before and after intervention. proBDNF did not present changes acutely nor after 6 weeks. Executive function presented a main effect of time at pre- and post-intervention time-points Stroop Word and Stroop Color and Coding subtest presented improved performance from pre- to post-acute exercise session, in both groups. In conclusion, executive function improvements and acute exercise session-induced increases in mBDNF concentration were found from pre- to post-exercise intervention similarly between MICT and HIIT in obese men.

Brain-derived neurotrophic factor precursor (proBDNF) plays a critical role in the pathogenesis and progression of various human diseases. Through its interaction with p75NTR and sortilin receptors, proBDNF promotes apoptosis, impairs synaptic plasticity, and contributes to the regulation of immune system function, inflammatory responses and cellular metabolic processes. proBDNF is widely distributed throughout the body, and as such, extensive research has demonstrated that proBDNF is significantly associated with the pathophysiological mechanisms underlying several diseases. In the present review, the mechanisms by which proBDNF contributes to different diseases are summarized to highlight its potential therapeutic and diagnostic implications. Specifically, the role of proBDNF in cognitive disorders, focusing on its effects on synaptic function and neural network dynamics, while analyzing the cascade reactions involving proBDNF and downstream effector molecules in inflammatory diseases, to elucidate its bidirectional regulatory effects in tumor initiation and progression. Furthermore, the function of proBDNF in neurogenesis, the mechanism by which it regulates the memory of fear, and enhances individual behavioral flexibility is discussed. Finally, the potential of proBDNF as a biomarker for disease diagnosis and the therapeutic prospects of targeting it using monoclonal antibodies are highlighted while also proposing future research directions. The present review can serve as a reference for translational medical research on proBDNF and its receptors.

An emerging body of data suggests that the early onset of Alzheimer's disease (AD) is associated with decreased brain-derived neurotrophic factor (BDNF). Because BDNF plays a critical role in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, the up-regulation of BDNF may rescue cognitive impairments and learning deficits in AD. In the present study, we investigated the effects of hippocampal BDNF in a rat model of AD produced by a ventricle injection of amyloid-β1-42 (Aβ1-42). We found that a ventricle injection of Aβ1-42 caused learning deficits in rats subjected to the Morris water maze and decreased BDNF expression in the hippocampus. Chronic intra-hippocampal BDNF administration rescued learning deficits in the water maze, whereas infusions of NGF and NT-3 did not influence the behavioral performance of rats injected with Aβ1-42. Furthermore, the BDNF-related improvement in learning was ERK-dependent because the inhibition of ERK, but not JNK or p38, blocked the effects of BDNF on cognitive improvement in rats injected with Aβ1-42. Together, our data suggest that the up-regulation of BDNF in the hippocampus via activation of the ERK signaling pathway can ameliorate Aβ1-42-induced learning deficits, thus identifying a novel pathway through which BDNF protects against AD-related cognitive impairments. The results of this research may shed light on a feasible therapeutic approach to control the progression of AD.

Brain-derived neurotrophic factor (BDNF) plays a crucial role in the survival, differentiation, growth, and plasticity of the central nervous system (CNS). Post-traumatic stress disorder (PTSD) is a complex syndrome that affects CNS function. Evidence indicates that changes in peripheral levels of BDNF may interfere with stress. However, the results are mixed. This study investigates whether blood levels of BDNF in patients with post-traumatic stress disorder (PTSD) are different. We conducted a systematic search in the major electronic medical databases from inception through September 2019 and identified Observational studies that measured serum levels of BDNF in patients with PTSD compared to controls without PTSD. 20 studies were eligible to be included in the present meta-analysis. Subjects with PTSD (n = 909) showed lower BDNF levels compared to Non-PTSD controls (n = 1679) (SMD = 0.52; 95% confidence interval: 0.18 to 0.85). Subgroup meta-analyses confirmed higher levels of BDNF in patients with PTSD compared to non-PTSD controls in plasma, not serum, and in studies that used sandwich ELISA, not ELISA, for BDNF measurement. Meta-regressions showed no significant effect of age, gender, NOS, and sample size. PTSD patients had increased serum BDNF levels compared to healthy controls. Our finding of higher BDNF levels in patients with PTSD supports the notion that PTSD is a neuroplastic disorder.