BDNF as a pain modulator

At least some neurotrophins may be powerful modulators of synapses, thereby influencing short- and long-term synaptic efficiency. BDNF acts at central synapses in pain pathways both at spinal and supraspinal levels. Neuronal synthesis, subcellular storage/co-storage and release of BDNF at these synapses have been characterized on anatomical and physiological grounds, in parallel with trkB (the high affinity BDNF receptor) distribution. Histological and functional evidence has been provided, mainly from studies on acute slices and intact animals, that BDNF modulates fast excitatory (glutamatergic) and inhibitory (GABAergic/glycinergic) signals, as well as slow peptidergic neurotrasmission in spinal cord. Recent studies have unraveled some of the neuronal circuitries and mechanisms involved, highlighting the key role of synaptic glomeruli in lamina II as the main sites for such a modulation.     

β-Amyloid impairs axonal BDNF retrograde trafficking

The neurotrophin, brain-derived neurotrophic factor (BDNF), is essential for synaptic function, plasticity and neuronal survival. At the axon terminal, when BDNF binds to its receptor, tropomyosin-related kinase B (TrkB), the signal is propagated along the axon to the cell body, via retrograde transport, regulating gene expression and neuronal function. Alzheimer disease (AD) is characterized by early impairments in synaptic function that may result in part from neurotrophin signaling deficits. Growing evidence suggests that soluble β-amyloid (Aβ) assemblies cause synaptic dysfunction by disrupting both neurotransmitter and neurotrophin signaling. Utilizing a novel microfluidic culture chamber, we demonstrate a BDNF retrograde signaling deficit in AD transgenic mouse neurons (Tg2576) that can be reversed by γ-secretase inhibitors. Using BDNF-GFP, we show that BDNF-mediated TrkB retrograde trafficking is impaired in Tg2576 axons. Furthermore, Aβ oligomers alone impair BDNF retrograde transport. Thus, Aβ reduces BDNF signaling by impairing axonal transport and this may underlie the synaptic dysfunction observed in AD.     

Down-regulation of the Trk-B signal pathway: the possible pathogenesis of major depression

Major depressive disorder (MDD) is a common mental disease with unknown etiology. Recent studies have suggested that decreased brain-derived neurotrophic factor (BDNF) may be implicated in the pathogenesis of MDD. Instead of a decrease in central BDNF, however, studies utilizing genetic depression animal models have found elevated levels of the factor. In the brain, BDNF exerts its influence chiefly by signaling through tyrosine receptor kinase B (Trk-B). In this report, it is suggested that Trk-B pathway down-regulation may be the major pathogenesis for MDD, while stress, which may reduce central BDNF, acts as a precipitation factor to further dampen central BDNF activity and contribute to the development of depression. Further, several possible mechanisms of Trk-B pathway down-regulation, and the implications for this down-regulation in MDD are discussed.     

Visualizing synapse formation in arborizing optic axons in vivo: dynamics and modulation by BDNF

Dynamic developmental changes in axon arbor morphology may directly reflect the formation, stabilization and elimination of synapses. We used dual-color imaging to study, in the live, developing animal, the relationship between axon arborization and synapse formation at the single cell level, and to examine the participation of brain-derived neurotrophic factor (BDNF) in synaptogenesis. Green fluorescent protein (GFP)-tagged synaptobrevin II served as a marker to visualize synaptic sites in individual fluorescently labeled Xenopus optic axons. Time-lapse confocal microscopy revealed that although most synapses remain stable, synapses are also formed and eliminated as axons branch and increase their complexity. Most new branches originated at GFP-labeled synaptic sites. Increasing BDNF levels significantly increased both axon arborization and synapse number, with BDNF increasing synapse number per axon terminal. The ability to visualize central synapses in real time provides insights about the dynamic mechanisms underlying synaptogenesis, and reveals BDNF as a modulator of synaptogenesis in vivo.     

Injection of brain-derived neurotrophic factor in the rostral ventrolateral medulla increases arterial blood pressure in anaesthetized rats

Brain-derived neurotrophic factor (BDNF) is a unique neurotrophin which not only supports the development of neurons but also modulates the synaptic activity in a number of neuronal systems. BDNF is synthesized in neurons, anterogradely transported and released from nerve terminals and exerts acute effects on synaptic transmission in both peripheral and central nervous systems. Previous studies have shown that BDNF is distributed in several groups of neurons in the brain stem which regulate cardiovascular functions. Here we showed that injection of BDNF (40-400 ng/100 nl) into the rostral ventrolateral medulla resulted in a significant increase in arterial blood pressure (Delta35.5+/-3.5 mmHg) in rats. The duration of change in blood pressure was 145+/-40 s with a latency of 3-5 s. There was no significant effect on the heart rate. The injection of glutamate as a positive control also triggered an increase in blood pressure. Injection of phosphate-buffered saline as a control or the same amount of nerve growth factor did not cause significant changes in blood pressure in different preparations. Immunohistochemistry showed that the nerve terminals immunoreactive for BDNF were localized in several brain stem regions and terminate around spinal projection neurons in the rostral ventrolateral medulla. Neurons in the rostral ventrolateral medulla can uptake exogenous BDNF and express the high affinity receptor trkB.From these results we suggest that BNDF in the medulla may play a role in the regulation of blood pressure.     

Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease

Brain-derived neurotrophic factor (BDNF) is a small dimeric protein, structurally related to nerve growth factor, which is abundantly and widely expressed in the adult mammalian brain. BDNF has been found to promote survival of all major neuronal types affected in Alzheimer's disease and Parkinson's disease, like hippocampal and neocortical neurons, cholinergic septal and basal forebrain neurons, and nigral dopaminergic neurons. In this article, we summarize recent work on the molecular and cellular biology of BDNF, including current ideas about its intracellular trafficking, regulated synthesis and release, and actions at the synaptic level, which have considerably expanded our conception of BDNF actions in the central nervous system. But our primary aim is to review the literature regarding BDNF distribution in the human brain, and the modifications of BDNF expression which occur in the brain of individuals with Alzheimer's disease and Parkinson's disease. Our knowledge concerning BDNF actions on the neuronal populations affected in these pathological states is also reviewed, with an aim at understanding its pathogenic and pathophysiological relevance.     

Cortical neurons from intrauterine growth retardation rats exhibit lower response to neurotrophin BDNF

Intrauterine growth retardation (IUGR) is putatively involved in the pathophysiology of schizophrenia. The animal model of IUGR induced by synthetic thromboxane A2 (TXA2) is useful to clarify the effect of IUGR on pups’ brains, however, analysis at the cellular level is still needed. Brain-derived neurotrophic factor (BDNF), which plays a role in neuronal survival and synaptic plasticity in the central nervous system (CNS), may also be associated with schizophrenia. However, the possible relationship between IUGR and BDNF function remains unclear. Here, we examined how IUGR by TXA2 impacts BDNF function by using dissociated cortical neurons. We found that, although BDNF levels in cultured neurons from the cerebral cortex of low birth weight pups with IUGR were unchanged, TrkB (BDNF receptor) was decreased compared with control-rats. BDNF-stimulated MAPK/ERK1/2 and PI3K/Akt pathways, which are downstream intracellular signaling pathways of TrkB, were repressed in IUGR-rat cultures. Expression of glutamate receptors such as GluA1 and GluN2A was also suppressed in IUGR-rat cultures. Furthermore, in IUGR-rat cultures, anti-apoptotic protein Bcl2 was decreased and BDNF failed to prevent neurons from cell death caused by serum-deprivation. Taken together, IUGR resulted in reductions in cell viability and in synaptic function following TrkB down-regulation, which may play a role in schizophrenia-like behaviors.     

TrkB inhibition as a therapeutic target for CNS-related disorders

The interaction of brain-derived neurotrophic factor (BDNF) with its tropomyosin-related kinase receptor B (TrkB) is involved in fundamental cellular processes including neuronal proliferation, differentiation and survival as well as neurotransmitter release and synaptic plasticity. TrkB signaling has been widely associated with beneficial, trophic effects and many commonly used psychotropic drugs aim to increase BDNF levels in the brain. However, it is likely that a prolonged increased TrkB activation is observed in many pathological conditions, which may underlie the development and course of clinical symptoms. Interestingly, genetic and pharmacological studies aiming at decreasing TrkB activation in rodent models mimicking human pathology have demonstrated a promising therapeutic landscape for TrkB inhibitors in the treatment of various diseases, e.g. central nervous system (CNS) disorders and several types of cancer. Up to date, only a few selective and potent TrkB inhibitors have been developed. As such, the use of crystallography and in silico approaches to model BDNF-TrkB interaction and to generate relevant pharmacophores represent powerful tools to develop novel compounds targeting the TrkB receptor.     

Activity-dependent expression of brain-derived neurotrophic factor in dendrites: facts and open questions

Long-lasting synaptic changes in transmission and morphology at the basis of memory storage, require delivery of newly synthesized proteins to affected synapses. Although many of these proteins are generated in the cell body, several key molecules for plasticity can be delivered in the form of silent mRNAs at synapses in extra somatic compartments where they are locally translated. One of such mRNAs encodes brain-derived neurotrophic factor (BDNF), a key molecule in neuronal development, learning and memory. A single BDNF protein is produced from several splice variants having a different 5' untranslated region. These mRNA variants have a different subcellular localization (soma, proximal or distal dendritic compartment) and may represent a spatial code for a local control of BDNF availability. This review will highlight current knowledge on the mechanisms of spatial and temporal regulation of activity-dependent BDNF mRNA localization in dendrites in relation with synaptic plasticity.     

Collaboration of fibronectin matrix and neurotrophin in regulating spontaneous transmitter release at developing neuromuscular synapses in Xenopus cell cultures

Integrins mediate cell-extracellular matrix connection and are particularly important during neuronal development. We here investigated the regulation of fibronectin (FN) matrix and neurotrophins on the embryonic synaptic transmission. Spontaneous synaptic currents (SSCs) were recorded from innervated myocytes of 1-day-old Xenopus cultures by whole-cell recordings. The SSC increasing action of alpha,beta-methylene adenosine triphosphate was enhanced in neurons grown on FN substratum, which was further potentiated by chronic treatment with brain-derived neurotrophic factor (BDNF). The SSC increasing action of thapsigargin, carbonyl cyanide m-chlorophenylhydrazone and N-methyl-D-aspartate was also markedly potentiated in neurons grown on FN-coated glass coverslips and chronically treated with BDNF. FN matrix or BDNF alone only exerts slight potentiation on the SSC increasing action of these three drugs. Our results suggest that FN matrix can collaborate with neurotrophin in regulating synaptic transmission at developing motoneurons, which may play an important role in the maturation of embryonic neuromuscular junction.     

Differentiation/maturation of neuropeptide Y neurons in the corpus callosum is promoted by brain-derived neurotrophic factor in mouse brain slice cultures

Neuropeptide Y (NPY) is widely distributed throughout both the central and peripheral nervous systems in mammals, and plays a role in various functions such as neural modifications affecting feeding, cardiovascular dynamics, or neural diseases. Many NPY neurons exist not only in gray matter in the central nervous system or ganglia in the peripheral system, but also in white matter such as the corpus callosum (cc) especially during development. The functions and regulation of callosal NPY neurons are not well understood, though NPY neurons in the cerebral cortex or hypothalamus are known to be regulated by neurotrophic factors such as brain-derived neurotrophic factor (BDNF). We examined the effect of BDNF on NPY neurons in the cc using organotypic slice cultures to clarify the regulation of callosal NPY neurons. A 3-week administration of BDNF significantly increased the number of NPY-immunopositive neuronal cell bodies and fibers in the cc rather than in the cerebral cortex as assessed with immunohistochemistry. Electron microscopy demonstrated that the NPY immunoreactivity mainly occurred in the regions associated with accumulating synaptic or cored vesicles. NPY-positive fibers had some contacts with several other neuronal fibers and glial processes. BDNF affected these fine structures of NPY neuronal fibers in the cc. These results suggest that BDNF takes part in the development, maturation, and maintenance of NPY neurons in the cc.     

Recent progress in studies of neurotrophic factors and their clinical implications

 Neurotrophic factors are endogenous soluble proteins that regulate long-term survival and differentiation of neurons of the peripheral and central nervous systems. These factors play an important role in the structural integrity of the nervous system, and therefore are good candidates as therapeutic agents for neurodegenerative diseases. However, recent studies have revealed some unexpected, novel roles of neurotrophic factors. Of particular significance is the discovery of the new functions of brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF). Physiological experiments indicate that BDNF may serve as regulatory factors for synaptic transmission as well as for learning and memory. Gene targeting studies demonstrate that GDNF may be essential for development of the enteric nervous system (ENS) and kidney organogenesis. These results not only provide new insights into our understanding of the function of neurotrophic factors but may also have significant implications in the therapeutic usages of neurotrophic factors. Received: 12 November 1996 / Accepted: 26 March 1997     

Long-term effects of brain-derived neurotrophic factor on the frequency of inhibitory synaptic events in the rat superficial dorsal horn

Chronic constriction injury (CCI) of rat sciatic nerve produces a specific pattern of electrophysiological changes in the superficial dorsal horn that lead to central sensitization that is associated with neuropathic pain. These changes can be recapitulated in spinal cord organotypic cultures by long term (5–6 days) exposure to brain-derived neurotrophic factor (BDNF) (200 ng/ml). Certain lines of evidence suggest that both CCI and BDNF increase excitatory synaptic drive to putative excitatory neurons while reducing that to putative inhibitory interneurons. Because BDNF slows the rate of discharge of synaptically-driven action potentials in inhibitory neurons, it should also decrease the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) throughout the superficial dorsal horn. To test this possibility, we characterized superficial dorsal horn neurons in organotypic cultures according to five electrophysiological phenotypes that included tonic, delay and irregular firing neurons. Five to 6 days of treatment with 200 ng/ml BDNF decreased sIPSC frequency in tonic and irregular neurons as might be expected if BDNF selectively decreases excitatory synaptic drive to inhibitory interneurons. The frequency of sIPSCs in delay neurons was however increased. Further analysis of the action of BDNF on tetrodotoxin-resistant miniature inhibitory postsynaptic currents (mIPSC) showed that the frequency was increased in delay neurons, unchanged in tonic neurons and decreased in irregular neurons. BDNF may thus reduce action potential frequency in those inhibitory interneurons that project to tonic and irregular neurons but not in those that project to delay neurons.     

Ultrastructural localization of brain-derived neurotrophic factor in rat primary sensory neurons

In a previous study we have shown that brain-derived neurotrophic factor (BDNF) is present in a subpopulation of small- to medium-sized sensory neurons in the dorsal root ganglia (DRG) and is anterogradely transported in both the peripheral and central processes. Within the spinal cord, BDNF is localized to varicosities of sensory nerve terminals in laminae I and II of the dorsal horn. This study raised the question of whether BDNF is localized in synaptic vesicles of the afferent nerve terminals. Using immunohistochemical and immunocytochemical techniques we have now investigated the ultrastructural localization of BDNF in the spinal cord of the rat. In addition, its colocalization with the low affinity neurotrophin receptor, p75, and calcitonin gene related peptide (CGRP) was also investigated. In lamina II of the spinal cord, BDNF immunoreactivity was restricted to nerve terminals. The reaction product appeared associated with dense-cored and clear vesicles of terminals superficial laminae. Double labelling experiments at the light microscopic level showed that 55% of BDNF immunoreactive neurons in DRG are colocalized with CGRP and many nerve terminals in laminae I and II of the spinal cord contained both BDNF and CGRP immunoreactivities. The results of double labelling at the ultrastructural level showed that most BDNF-ir (immunoreactive) nerve terminals contained CGRP or the low affinity neurotrophin receptor, p75, but not vice versa. These results point to the conclusion that BDNF may be released in parallel with neurotransmitters from nerve terminals in the spinal cord from a subpopulation of nociceptive primary afferents.     

BDNF signaling in the formation, maturation and plasticity of glutamatergic and GABAergic synapses

In the past 15 years numerous reports provided strong evidence that brain-derived neurotrophic factor (BDNF) is one of the most important modulators of glutamatergic and GABAergic synapses. Remarkable progress regarding localization, kinetics, and molecular mechanisms of BDNF secretion has been achieved, and a large number of studies provided evidence that continuous extracellular supply of BDNF is important for the proper formation and functional maturation of glutamatergic and GABAergic synapses. BDNF can play a permissive role in shaping synaptic networks, making them more susceptible for the occurrence of plastic changes. In addition, BDNF appears to be also an instructive factor for activity-dependent long-term synaptic plasticity. BDNF release just in response to synaptic stimulation might be a molecular trigger to convert high-frequency synaptic activity into long-term synaptic memories. This review attempts to summarize the current knowledge in synaptic secretion and synaptic action of BDNF, including both permissive and instructive effects of BDNF in synaptic plasticity.     

Exercise-induced brain-derived neurotrophic factor expression: Therapeutic implications for Alzheimer’s dementia

Emerging evidence indicates that moderate intensity aerobic exercise is positively correlated with cognitive function and memory. However, the exact mechanisms underlying such improvements remain unclear. Recent research in animal models allows proposition of a pathway in which brain-derived neurotrophic factor (BDNF) is a key mediator. This perspective draws upon evidence from animal and human studies to highlight such a mechanism whereby exercise drives synthesis and accumulation of neuroactive metabolites such as myokines and ketone bodies in the periphery and in the hippocampus to enhance BDNF expression. BDNF is a neurotrophin with well-established properties of promoting neuronal survival and synaptic integrity, while its influence on energy transduction may provide the crucial link between inherent vascular and metabolic benefits of exercise with enhanced brain function. Indeed, BDNF mRNA and protein is robustly elevated in rats following periods of voluntary exercise. This was also correlated with improved spatial memory, while such benefits were abolished upon inhibition of BDNF signaling. Similarly, both BDNF and cardiovascular fitness arising from aerobic exercise have been positively associated with hippocampal volume and function in humans. We postulate that exercise will attenuate cortical atrophy and synaptic loss inherent to neurodegenerative disorders - many of which also exhibit aberrant down-regulation of BDNF. Thus, the proposed link between BDNF, exercise and cognition may have critical therapeutic implications for the prevention and amelioration of memory loss and cognitive impairment in Alzheimer’s disease and associated dementias.     

脑源性神经营养因子及其在中枢神经损伤修复中的作用

脑源性神经营养因子(BDNF)属于神经营养因子家族成员,与原肌球蛋白相关激酶B(trkB)受体相结合调节神经细胞的生存,生长以及突触传递。BDNF基因具有多个启动子及调节元件,其表达受神经活动和多种激素水平的调控。当大脑因外伤、缺血、压力等原因受损时,BDNF在中枢神经系统中表达增加,通过延缓凋亡、促进新生及增强突触传递等方法使受损神经细胞得以修复。本文对BDNF基因、BDNF表达的调控、BDNF的分子结构及其受体、BDNF的信号传导等做了介绍,阐述了BDNF在中枢神经损伤修复中的作用。     

The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that mediates synaptic plasticity and excitability in the CNS. Recent evidence has shown that increased BDNF levels can lead to hyperexcitability and epileptiform activities, while suppression of BDNF function in transgenic mice or by antagonist administration retards the development of seizures. However, several groups, including our own, have reported that increasing BDNF levels by continuous intrahippocampal infusion inhibits epileptogenesis. It is possible that the continuous administration of BDNF produces a down-regulation of its high-affinity TrkB receptor, leading to a decrease of neuronal responsiveness to BDNF. If so, then animals should respond differently to bolus injections of BDNF, which presumably do not alter Trk expression, compared with continuous infusion. To test this hypothesis, we compared the effects of intrahippocampal BDNF continuous infusion and bolus injections on kindling induction. We showed that continuous infusion of BDNF inhibited the development of behavioral seizures and decreased the level of phosphorylated Trks or TrkB receptors. In contrast, multiple bolus microinjections of BDNF accelerated kindling development and did not affect the level of phosphorylated Trks or TrkB receptors. Our results indicate that different administration protocols yield opposite effects of BDNF on neuronal excitability, epileptogenesis and Trk expression. Unlike nerve growth factor and neurotrophin-3, which affect mossy fiber sprouting, we found that BDNF administration had no effect on the mossy fiber system in naive or kindled rats. Such results suggest that the effects of BDNF on epileptogenesis are not modulated by its effect on sprouting, but rather by its effects on excitability.