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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.

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.

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.

Recent clinical studies demonstrate that serum levels of brain-derived neurotrophic factor (BDNF) are significantly decreased in patients with major depressive disorder (MDD) and that antidepressant treatments reverse this effect, indicating that serum BDNF is a biomarker of MDD. These findings raise the possibility that serum BDNF may also have effects on neuronal activity and behavior, but the functional significance of altered serum BDNF is unknown. To address this issue, we determined the influence of peripheral BDNF administration on depression- and anxiety-like behavior, including the forced swim test (FST), chronic unpredictable stress (CUS)/anhedonia, novelty-induced hypophagia (NIH) test, and elevated-plus maze (EPM). Furthermore, we examined adult hippocampal neurogenesis as well as hippocampal and striatal expression of BDNF, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), in order to determine whether peripherally administered BDNF produces antidepressant-like cellular responses in the brain. Peripheral BDNF administration increased mobility in the FST, attenuated the effects of CUS on sucrose consumption, decreased latency in the NIH test, and increased time spent in the open arms of an EPM. Moreover, adult hippocampal neurogenesis was increased after chronic, peripheral BDNF administration. We also found that BDNF levels as well as expression of pCREB and pERK were elevated in the hippocampus of adult mice receiving peripheral BDNF. Taken together, these results indicate that peripheral/serum BDNF may not only represent a biomarker of MDD, but also have functional consequences on molecular signaling substrates, neurogenesis, and behavior.

Studies suggest that dysfunction of brain-derived neurotrophic factor (BDNF) is a possible contributor to the pathology and symptoms of Alzheimer’s disease (AD). Several studies report reduced peripheral blood levels of BDNF in AD, but findings are inconsistent. This study sought to quantitatively summarize the clinical BDNF data in patients with AD and mild cognitive impairment (MCI, a prodromal stage of AD) with a meta-analytical technique. A systematic search of Pubmed, PsycINFO and the Cochrane Library identified 29 articles for inclusion in the meta-analysis. Random-effects meta-analysis showed that patients with AD had significantly decreased baseline peripheral blood levels of BDNF compared with healthy control (HC) subjects (24 studies, Hedges' g =−0.339, 95% confidence interval (CI)=−0.572 to −0.106, P =0.004). MCI subjects showed a trend for decreased BDNF levels compared with HC subjects (14 studies, Hedges' g =−0.201, 95% CI=−0.413 to 0.010, P =0.062). No differences were found between AD and MCI subjects in BDNF levels (11 studies, Hedges' g =0.058, 95% CI=−0.120 to 0.236, P =0.522). Interestingly, the effective sizes and statistical significance improved after excluding studies with reported medication in patients (between AD and HC: 18 studies, Hedges' g =−0.492, P <0.001; between MCI and HC: 11 studies, Hedges' g =−0.339, P =0.003). These results strengthen the clinical evidence that AD or MCI is accompanied by reduced peripheral blood BDNF levels, supporting an association between the decreasing levels of BDNF and 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.

GABA is a pain Neuropathic pain, one of the most debilitating of all pain states, often arises from injury to a peripheral nerve that depends on activation of a specific cell type known as microglia. This prompts the question, how do the microglia signal to spinal pain neurons? Coull et al . have now identified the biophysical mechanism by which microglia, activated by ATP, cause hyperexcitability of spinal neurons. The microglia release brain-derived neurotrophic factor, which alters chloride ion distribution across the plasma membrane of neurons in lamina I of the spinal cord. This results in the neurotransmitter, GABA, activating (rather than inhibiting) these cells that form part of a major pathway that signals pain. A collection of recent reprints on neuropathic pain, taken from Nature Publishing Group journals is, now available online via tinyurl.com/dzw86. Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord 1 , 2 , 3 . Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury 4 . Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential ( E anion ) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (γ-amino butyric acid), as has been shown to occur after peripheral nerve injury 5 . Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E anion . Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E anion shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E anion . Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia–neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.