The p75 receptor is required for BDNF-induced differentiation of neural precursor cells

Epidermal growth factor (EGF)-treated neurospheres from fetal forebrain contain multipotential cells capable of neuronal, astrocytic, and oligodendroglial differentiation. These neural precursor cells express the TrkB as well as the neurotrophin receptor p75 (p75NTR), suggesting that they are BDNF responsive. In this study, we test whether the p75NTR plays a role in the differentiation of these neural precursor cells in vitro. Activation of the TrkB and the p75NTR by the addition of BDNF facilitates neuronal commitment and marked neurite genesis. However, no promotion of neuronal commitment by BDNF was observed in the neural precursor cells from mice carrying a mutation in the p75NTR gene. In addition, we observed a significant increase in the number of nestin-positive cells and the proliferation of the cells lacking functional p75NTR. These findings suggest that the p75NTR is required for proper neuronal fate decision as well as the differentiation of the neural precursor cells.     

Neurogenic and Neurotrophic Effects of BDNF Peptides in Mouse Hippocampal Primary Neuronal Cell Cultures

The level of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is down regulated in Alzheimer’s disease (AD), Parkinson’s disease (PD), depression, stress, and anxiety; conversely the level of this neurotrophin is increased in autism spectrum disorders. Thus, modulating the level of BDNF can be a potential therapeutic approach for nervous system pathologies. In the present study, we designed five different tetra peptides (peptides B-1 to B-5) corresponding to different active regions of BDNF. These tetra peptides were found to be non-toxic, and they induced the expression of neuronal markers in mouse embryonic day 18 (E18) primary hippocampal neuronal cultures. Additionally, peptide B-5 induced the expression of BDNF and its receptor, TrkB, suggesting a positive feedback mechanism. The BDNF peptides induced only a moderate activation (phosphorylation at Tyr 706) of the TrkB receptor, which could be blocked by the Trk’s inhibitor, K252a. Peptide B-3, when combined with BDNF, potentiated the survival effect of this neurotrophin on H₂O₂-treated E18 hippocampal cells. Peptides B-3 and B-5 were found to work as partial agonists and as partial antagonists competing with BDNF to activate the TrkB receptor in a dose-dependent manner. Taken together, these results suggest that the described BDNF tetra peptides are neurotrophic, can modulate BDNF signaling in a partial agonist/antagonist way, and offer a novel therapeutic approach to neural pathologies where BDNF levels are dysregulated.     

Lithium enhances the neuronal differentiation of neural progenitor cells in vitro and after transplantation into the avulsed ventral horn of adult rats through the secretion of brain-derived neurotrophic factor

This study was undertaken to elucidate the molecular mechanisms by which lithium regulates the development of spinal cord-derived neural progenitor cells (NPCs) in vitro and after transplanted in vivo . Our results show that lithium at the therapeutic concentration significantly increases the proliferation and neuronal differentiation of NPCs in vitro. Specific ELISAs, western blotting, and quantitative real-time RT-PCR assays demonstrate that lithium treatment significantly elevates the expression and production of brain-derived neurotrophic factor (BDNF) by NPCs in culture. Application of a BDNF neutralizing antibody in culture leads to a marked reduction in the neurogenesis of lithium-treated NPCs to the control level. However, it shows no effects on the proliferation of lithium-treated NPCs. These findings suggest that the BDNF pathway is possibly involved in the supportive role of lithium in inducing NPC neurogenesis but not proliferation. This study also provides evidence that lithium is able to elevate the neuronal generation and BDNF production of NPCs after transplantation into the adult rat ventral horn with motoneuron degeneration because of spinal root avulsion, which highlights the therapeutic potential of lithium in cell replacement strategies for spinal cord injury because of its ability to promote neuronal differentiation and BDNF production of grafted NPCs in the injured spinal cord.     

BDNF-Dependent Accumulation of Palmitoleic Acid in CNS Neurons

Although it is known that brain-derived neurotrophic factor (BDNF) plays a critical role in neuronal survival and differentiation, its effect on lipid homeostasis is poorly understood. To understand them, we here investigated the effect of BDNF on the fatty acid composition of primary neurons. A detailed analysis of the fatty acid composition of BDNF-stimulated primary neurons revealed that BDNF treatment led to a significant and selective increase in intracellular palmitoleic acid (PLO) levels. Correspondingly, BDNF induced the expression of the enzyme responsible for PLO synthesis [stearoyl-CoA desaturase-1]. In addition, this increase was suppressed by K252a, an inhibitor for tropomyosin-related kinase (Trk) receptors, indicating that BDNF-dependent increase in the PLO was mediated through the activation of TrkB. Further, PLO in culture media was reduced by BDNF treatment. This result suggested that BDNF suppressed extracellular release of PLO. Taken together, these data indicate that BDNF increases intracellular PLO both by activating its biosynthesis and by suppressing its extracellular release.     

Stable isotopic labeling by amino acids in cultured primary neurons: application to brain-derived neurotrophic factor-dependent phosphotyrosine-associated signaling

Cultured primary neurons are a well established model for the study of neuronal function in vitro. Here we demonstrated that stable isotope labeling by amino acids in cell culture (SILAC) can be applied to a differentiated, non-dividing cell type such as primary neurons, and we applied this technique to assess changes in the neuronal phosphotyrosine proteome in response to stimulation by brain-derived neurotrophic factor (BDNF), an important molecule for the development and regulation of neuronal connections. We found that 13 proteins had SILAC ratios above 1.50 or below 0.67 in phosphotyrosine immunoprecipitations comparing BDNF-treated and control samples, and an additional 18 proteins had ratios above 1.25 or below 0.80. These proteins include TrkB, the receptor tyrosine kinase for BDNF, and others such as hepatocyte growth factor-regulated tyrosine kinase substrate and signal-transducing adaptor molecule, which are proteins known to regulate intracellular trafficking of receptor tyrosine kinases. These results demonstrate that the combination of primary neuronal cell culture and SILAC can be a powerful tool for the study of the proteomes of neuronal molecular and cellular dynamics.     

Role of the neurotrophic factors BDNF and NGF in the commitment of pluripotent neural crest cells.

Since trophic factors are increasingly recognized as playing a role in some decision-making steps during development, the influence of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) on the commitment of pluripotent neural crest cells was investigated by in vitro clonal analysis. BDNF caused an increase of up to 21-fold in the number of sensory neuron precursors per colony without a corresponding increase in the total number of cells. By contrast, BDNF treatment caused an equivalent decrease in the number of undifferentiated cells per colony. The data suggest that BDNF, but not NGF, directs pluripotent neural crest cells to differentiate along the primary sensory neuron lineage.     

The neurotrophins and CNTF: specificity of action towards PNS and CNS neurons.

The availability of relatively large amounts of nerve growth factor (NGF) has allowed extensive in vitro and in vivo characterization of the neuronal specificity of this neurotrophic factor. The restricted neuronal specificity of NGF (sympathetic neurons, neural crest-derived sensory neurons, basal forebrain cholinergic neurons) has long predicted the existence of other neurotrophic factors possessing different neuronal specificities. Whereas there have been many reports of "activities" distinct from NGF, full characterization of such molecules has been hampered by their extremely low abundance. The recent molecular cloning of brain-derived neurotrophic factor (BDNF) revealed that this protein is closely related to NGF and suggested that these two factors might be members of an even larger gene family. A PCR cloning strategy based on homologies between NGF and BDNF has allowed us to identify and clone a third member of the NGF family which we have termed neurotrophin-3 (NT-3). The establishment of suitable expression systems has now made available sufficient quantities of these proteins to allow us to begin to establish the neuronal specificity of each member of the neurotrophin family, and the role of each in development, maintenance and repair of the PNS and CNS. Using primary cultures of various PNS and CNS regions of the developing chick and rat, and Northern blot analysis, we describe novel neuronal specificities of BDNF, NT-3 and an unrelated neurotrophic factor-ciliary neurotrophic factor (CNTF).     

The lighter side of BDNF

Brain-derived neurotrophic factor (BDNF) mediates energy metabolism and feeding behavior. As a neurotrophin, BDNF promotes neuronal differentiation, survival during early development, adult neurogenesis, and neural plasticity; thus, there is the potential that BDNF could modify circuits important to eating behavior and energy expenditure. The possibility that "faulty" circuits could be remodeled by BDNF is an exciting concept for new therapies for obesity and eating disorders. In the hypothalamus, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are extensively expressed in areas associated with feeding and metabolism. Hypothalamic BDNF and TrkB appear to inhibit food intake and increase energy expenditure, leading to negative energy balance. In the hippocampus, the involvement of BDNF in neural plasticity and neurogenesis is important to learning and memory, but less is known about how BDNF participates in energy homeostasis. We review current research about BDNF in specific brain locations related to energy balance, environmental, and behavioral influences on BDNF expression and the possibility that BDNF may influence energy homeostasis via its role in neurogenesis and neural plasticity.     

Design of a conformationally defined and proteolytically stable circular mimetic of brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of neurotrophic factors. BDNF has long been recognized to have potential for the treatment of a variety of human neurodegenerative diseases. However, clinical trials with recombinant BDNF have yet to yield success, leading to the suggestion that alternative means of harnessing BDNF actions for therapeutic use may be required. Here we describe an approach to create low molecular weight peptides that, like BDNF, promote neuronal survival. The peptides were designed to mimic a cationic tripeptide sequence in loop 4 of BDNF shown in previous studies to contribute to the binding of BDNF to the common neurotrophin receptor p75NTR. The best of these peptides, the cyclic pentapeptide 2 (cyclo(-D-Pro-Ala-Lys-Arg-)), despite being of low molecular weight (Mr 580), was found to be an effective promoter of the survival of embryonic chick dorsal root ganglion sensory neurons in vitro (maximal survival, 68 +/- 3% of neurons supported by BDNF). Pentapeptide 2 did not affect the phosphorylation of either TrkB (the receptor tyrosine kinase for BDNF) or the downstream signaling molecule MAPK, indicating that its mechanism of neuronal survival action is independent of TrkB. NMR studies reveal that pentapeptide 2 adopts a well defined backbone conformation in solution. Furthermore, pentapeptide 2 was found to be effectively resistant to proteolysis when incubated in a solution of rat plasma in vitro. These properties of pentapeptide 2 (low molecular weight, appropriate pharmacological actions, a well defined solution conformation, and proteolytic stability) render it worthy of further investigation, either as a template for the further design of neuronal survival promoting agents or as a lead compound with therapeutic potential in its own right.     

Placode and neural crest-derived sensory neurons are responsive at early developmental stages to brain-derived neurotrophic factor

The response of embryonic chick nodose ganglion (neural placode-derived) and dorsal root ganglion (neural crest-derived) sensory neurons to the survival and neurite-promoting activity of brain-derived neurotrophic factor (BDNF) was studied in culture. In dissociated, neuron-enriched cultures established from chick embryos between Day 6 (E6) and Day 12 (E12) of development, both nodose ganglion (NG) and dorsal root ganglion (DRG) neurons were responsive on laminin-coated culture dishes to BDNF. In the case of NG, BDNF elicited neurite outgrowth from 40 to 50% of the neurons plated at three embryonic ages; E6, E9, and E12. At the same ages, nerve growth factor (NGF) alone or in combination with BDNF, had little or no effect upon neurite outgrowth from NG neurons. The response of NG neurons to BDNF was dose dependent and was sustainable for at least 7 days in culture. Surprisingly, in view of a previous study carried out using polyornithine as a substrate for neuronal cell attachment, on laminin-coated dishes BDNF also sustained survival and neurite outgrowth from a high percentage (60-70%) of DRG neurons taken from E6 embryos. In marked contrast to NG neurons, the combined effect of saturating levels of BDNF and NGF activity on DRG neurons was greater than the effect of either agent alone at all embryonic ages studied. Under similar culture conditions, BDNF did not elicit survival and neurite outgrowth from paravertebral chain sympathetic neurons or parasympathetic ciliary ganglion neurons. We propose that primary sensory neurons, regardless of their embryological origin, are responsive to a "central-target" (CNS) derived neurotrophic factor--BDNF, while they are differentially responsive to "peripheral-target"-derived growth factors, such as NGF, depending on whether the neurons are of neural crest or placodal origin.     

体外诱导人骨髓间充质干细胞向多巴胺神经元分化的研究

通过体外诱导人骨髓间充质干细胞(bone marrow mesenchymal stemcells,BMSCs)向多巴胺(dopamine,DA)神经元分化,探讨人BMSCs来源的DA神经元的功能特征及其分化机制,为临床上细胞移植替代治疗诸如帕金森氏病(parkinson’sdisease,PD)等神经精神性疾病提供一种理想的细胞来源。通过密度梯度离心获取人骨髓中的单个核细胞,贴壁培养纯化BMSCs。50μmol/L脑源性神经营养因子(brain derivedneurotrophy factor,BDNF),10μmol/Lforskolin(FSK)和10μmol/LDA联合对BMSCs进行诱导。电子显微镜观察诱导2周后细胞是否具有神经元的超微结构特点;免疫细胞化学染色和RT-PCR检测DA神经元分化过程中的标志物酪氨酸羟化酶(tyrosine hydroxylase,TH)的表达以及转录因子Nurr1、Ptx3和Lmx1b的表达;高效液相色谱(highperformance liquid chromatogram,HPLC)检测诱导2周后的细胞多巴胺的释放水平。结果表明,诱导2周后,电镜下细胞胞浆中有大量密集的呈扁平囊状的粗面内质网及其间的一些游离核糖体以及神经微丝的形成。RT-PCR结果显示NSE(neuron specificenolase)、Nurr1、Ptx3、Lmx1b和TH的mRNA均有表达;免疫细胞化学染色结果表明诱导2周后TH阳性细胞(24·80±3·36)%的表达较诱导3d后(3·77±1·77)%明显提高(P<0·01);HPLC检测到诱导2周后的细胞DA释放水平[(1·22±0·36)μg/mL(n=6)]高于未经诱导的细胞[(0·75±0·22)μg/mL(n=6)(t=-2·79,P=0·038)]。由此得出,BDNF、FSK和DA可以在体外诱导人BMSCs向DA神经元分化,并具有DA神经元的功能特征,是临床用于治疗神经精神性疾病的理想细胞来源。     

Bio-composites composed of a solid free-form fabricated polycaprolactone and alginate-releasing bone morphogenic protein and bone formation peptide for bone tissue regeneration

Biomedical scaffolds should be designed with highly porous three-dimensional (3D) structures that have mechanical properties similar to the replaced tissue, biocompatible properties, and biodegradability. Here, we propose a new composite composed of solid free-form fabricated polycaprolactone (PCL), bone morphogenic protein (BMP-2) or bone formation peptide (BFP-1), and alginate for bone tissue regeneration. In this study, PCL was used as a mechanical supporting component to enhance the mechanical properties of the final biocomposite and alginate was used as the deterring material to control the release of BMP-2 and BFP-1. A release test revealed that alginate can act as a good release control material. The in vitro biocompatibilities of the composites were examined using osteoblast-like cells (MG63) and the alkaline phosphatase (ALP) activity and calcium deposition were assessed. The in vitro test results revealed that PCL/BFP-1/Alginate had significantly higher ALP activity and calcium deposition than the PCL/BMP-2/Alginate composite. Based on these findings, release-controlled BFP-1 could be a good growth factor for enhancement of bone tissue growth and the simple-alginate coating method will be a useful tool for fabrication of highly functional biomaterials through release–control supplementation.     

Activation of adenosine A2A receptor up-regulates BDNF expression in rat primary cortical neurons

As a member of neurotrophin family, brain derived neurotrophic factor (BDNF) plays critical roles in neuronal development, differentiation, synaptogenesis, and neural protection from the harmful stimuli. There have been reported that adenosine A2(A) receptor subtype is widely distributed in the brain regions, such as hippocampus, striatum, and cortex. Adenosine A2(A) receptor is colocalized with BDNF in brain regions and the functional interaction between A2(A) receptor stimulation and BDNF action has been suggested. In this study, we investigated the possibility that the activation of A2(A) receptor modulates BDNF production in rat primary cortical neuron. CGS21680, an adenosine A2(A) receptor agonist, induced BDNF expression and release. An antagonist against A2(A) receptor, ZM241385, prevented CGS21680-induced increase in BDNF production. A2(A) receptor stimulation induced the activation of Akt-GSK-3β signaling pathway and the blockade of the signaling pathway with specific inhibitors abolished the increase in BDNF production, possibly via modulation of ERK1/2-CREB pathway. The physiological roles of A2(A) receptor-induced BDNF production was demonstrated by the protection of neurons from the excitotoxicity and increased neurite extension as well as synapse formation from immature and mature neurons. Taken together, activation of A2(A) receptor regulates BDNF production in rat cortical neuron, which provides neuro-protective action.     

Induction of Angiogenesis by Matrigel Coating of VEGF-Loaded PEG/PCL-Based Hydrogel Scaffolds for hBMSC Transplantation

hBMSCs are multipotent cells that are useful for tissue regeneration to treat degenerative diseases and others for their differentiation ability into chondrocytes, osteoblasts, adipocytes, hepatocytes and neuronal cells. In this study, biodegradable elastic hydrogels consisting of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(ε-caprolactone) (PCL) scaffolds were evaluated for tissue engineering because of its biocompatibility and the ability to control the release of bioactive peptides. The primary cultured cells from human bone marrow are confirmed as hBMSC by immunohistochemical analysis. Mesenchymal stem cell markers (collagen type I, fibronectin, CD54, integrin1β, and Hu protein) were shown to be positive, while hematopoietic stem cell markers (CD14 and CD45) were shown to be negative. Three different hydrogel scaffolds with different block compositions (PEG:PCL=6:14 and 14:6 by weight) were fabricated using the salt leaching method. The hBMSCs were expanded, seeded on the scaffolds, and cultured up to 8 days under static conditions in Iscove’s Modified Dulbecco’s Media (IMDM). The growth of MSCs cultured on the hydrogel with PEG/PCL= 6/14 was faster than that of the others. In addition, the morphology of MSCs seemed to be normal and no cytotoxicity was found. The coating of the vascular endothelial growth factor (VEGF) containing scaffold with Matrigel slowed down the release of VEGF in vitro and promoted the angiogenesis when transplanted into BALB/c nude mice. These results suggest that hBMSCs can be supported by a biode gradable hydrogel scaffold for effective cell growth, and enhance the angiogenesis by Matrigel coating.     

Design of potent peptide mimetics of brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) has potential for the treatment of human neurodegenerative diseases. However, the general lack of success of neurotrophic factors in clinical trials has led to the suggestion that low molecular weight neurotrophic drugs may be better agents for therapeutic use. Here we describe small, dimeric peptides designed to mimic a pair of solvent-exposed loops important for the binding and activation of the BDNF receptor, trkB. The monomer components that make up the dimers were based on a monocyclic monomeric peptide mimic of a single loop of BDNF (loop 2) that we had previously shown to be an inhibitor of BDNF-mediated neuronal survival (O'Leary, P. D., and Hughes, R. A. (1998) J. Neurochem. 70, 1712-1721). Bicyclic dimeric peptides behaved as partial agonists with respect to BDNF, promoting the survival of embryonic chick sensory neurons in culture. We reasoned that the potency and/or efficacy of these compounds might be improved by reducing the conformational flexibility about their dimerizing linker. Thus, we designed a highly conformationally constrained tricyclic dimeric peptide and synthesized it using an efficient, quasi-one-pot approach. Although still a partial BDNF-like agonist, the tricyclic dimer was particularly potent in promoting neuronal survival in vitro (EC50 11 pm). The peptides described here, which are greatly reduced in size compared with the parent protein, could serve as useful lead compounds for the development of true neurotrophic drugs and indicate that the structure-based design approach could be used to obtain potent mimetics of other growth factors that dimerize their receptors.     

Neurotrophin signaling and visceral hypersensitivity

Neurotrophin family are traditionally recognized for their nerve growth promoting function and are recently identified as crucial factors in regulating neuronal activity in the central and peripheral nervous systems. The family members including nerve growth factor （NGF）, brain-derived neurotrophic factor （BDNF）, and neurotrophin-3 （NT-3） are reported to have distinct roles in the development and maintenance of sensory phenotypes in normal states and in the modulation of sensory activity in disease. This paper highlights receptor tyrosine kinase （Trk） -mediated signal transduction by which neurotrophins regulate neuronal activity in the visceral sensory reflex pathways with emphasis on the distinct roles of NGF and BDNF signaling in physiologic and pathophysiological processes. Viscero-visceral cross-organ sensitization exists widely in human diseases. The role of neurotrophins in mediating neural cross talk and interaction in primary afferent neurons in the dorsal root ganglia （DRG） and neurotrophin signal transduction in the context of cross-organ sensitization are also discussed.     

Brain-derived neurotrophic factor enhances depolarization-evoked glutamate release in cultured cortical neurons

Brain-derived neurotrophic factor (BDNF) has been reported to play an important role in neuronal plasticity. In this study, we examined the effect of BDNF on an activity-dependent synaptic function in an acute phase. First, we found that short-term treatment (10 min) with BDNF enhanced depolarization-evoked glutamate release in cultured cortical neurons. The enhancement diminished gradually according to the length of BDNF treatment. The BDNF-enhanced release did not require the synthesis of protein and mRNA. Both tetanus toxin and bafilomycin abolished the depolarization-evoked glutamate release with or without BDNF, indicating that BDNF acted via an exocytotic pathway. Next, we investigated the effect of BDNF on intracellular Ca(2+). BDNF potentiated the increase in intracellular Ca(2+) induced by depolarization. The Ca(2+) was derived from intracellular stores, because thapsigargin completely inhibited the potentiation. Furthermore, both thapsigargin and xestospongin C inhibited the effect of BDNF. These results suggested that the release of Ca(2+) from intracellular stores mediated by the IP(3) receptor was involved in the BDNF-enhanced glutamate release. Last, it was revealed that the enhancement of glutamate release by BDNF was dependent on the TrkB-PLC-gamma pathway. These results clearly demonstrate that short-term treatment with BDNF enhances an exocytotic pathway by potentiating the accumulation of intracellular Ca(2+) through intracellular stores.     

Cografted Wharton’s Jelly Cells-derived Neurospheres and BDNF Promote Functional Recovery After Rat Spinal Cord Transection

An animal model of transected spinal cord injury (SCI) was used to test the hypothesis that cografted human umbilical mesenchymal stem cells-derived neurospheres (HUMSC-NSs) and BDNF can promote morphologic and functional recoveries of injured spinal cord. In vitro, HUMSC-NSs terminally differentiated into higher percentages of cells expressing neuronal markers: β-tubulin III and MAP2ab by the supplement with BDNF. Following grafted into injured spinal cord, very few grafted cells survived in the HUMSC-NSs + BDNF-treated (<3%) and HUMSC-NSs-treated (<1%) groups. The survived cells were differentiated into various cells, which were confirmed by double staining of BrdU and neural or glia markers. In comparison, more grafted cells in the HUMSC-NSs + BDNF group transformed into mature neural-like cells, while more grafted cells in the HUMSC-NSs group transformed into oligodendrocyte-like cells. HUMSC-NSs + BDNF-treated group had more greatly improved BBB scores, compared with HUMSC-NSs-treated and medium-treated groups. Additionally, axonal regeneration showed significant improvement in rats receiving HUMSC-NSs + BDNF, compared with HUMSC-NSs-treated and medium-treated groups, as demonstrated by the NF-200-positive staining and Fluorogold (FG) retrograde tracing study. Lastly, a significant reduction in the percentage cavitation was seen in the two cell-treated groups compared with medium control group. These results means BDNF could promote the neural differentiation of HUMSC-NSs in vitro and in vivo. However, cellular replacement is unlikely to explain the improvement in functional outcome. The functional recovery might more rely on the axonal regeneration and neuroprotective action that active by the grafted cells. Cografted HUMSCs and BDNF is a potential therapy for SCI.     

BDNF-induced recruitment of TrkB receptor into neuronal lipid rafts: roles in synaptic modulation

Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity but the underlying signaling mechanisms remain unknown. Here, we show that BDNF rapidly recruits full-length TrkB (TrkB-FL) receptor into cholesterol-rich lipid rafts from nonraft regions of neuronal plasma membranes. Translocation of TrkB-FL was blocked by Trk inhibitors, suggesting a role of TrkB tyrosine kinase in the translocation. Disruption of lipid rafts by depleting cholesterol from cell surface blocked the ligand-induced translocation. Moreover, disruption of lipid rafts prevented potentiating effects of BDNF on transmitter release in cultured neurons and synaptic response to tetanus in hippocampal slices. In contrast, lipid rafts are not required for BDNF regulation of neuronal survival. Thus, ligand-induced TrkB translocation into lipid rafts may represent a signaling mechanism selective for synaptic modulation by BDNF in the central nervous system.     

Acute role of the brain-derived neurotrophic factor (BDNF) on the respiratory neural network activity in mice in vitro

In humans, several pathologies are associated with disturbances of the respiratory control, some of them including alteration in the brain-derived neurotrophic factor (BDNF) signalling pathway. BDNF has long been known as a neurotrophic factor involved in survival, differentiation and maintenance of neuronal populations in the peripheral and central nervous system. More recently BDNF has also been discovered to be a potent neuromodulator with acute effects on neuronal excitability and synaptic plasticity. Animals deleted for the gene encoding BDNF exhibit respiratory alteration suggesting an important but yet undefined role of the neurotrophin in respiratory rhythmogenesis either by a trophic and/or an acute action. The possibility that BDNF might exert an acute regulatory role on the rhythmic activity of the respiratory generator of the pre-B?tzinger complex has been recently examined in newborn mice in vitro. Results obtained, reviewed in the present paper, will help getting insights in respiratory rhythm regulatory mechanisms that involve BDNF signalling.