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Neurotrophins
Terms modified by Neurotrophins Selected AbstractsNeurotrophin 3 and its Receptor TrkC Immunoreactivity in Glucagon Cells of Buffalo PancreasANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 4 2003C. Lucini Summary Neurotrophin 3 (NT3), a member of the neurotrophin family, and its specific receptor tyrosine kinase C (TrkC) are involved in the differentiation, survival, and maintenance of many neuronal populations. Recently, NT3 and TrkC were also retained involved in the biology of non-neuronal tissues. In this study, we report the presence of NT3- and TrkC-immunoreactive cells in the endocrine pancreas of adult buffalos. They were usually distributed at the periphery of islets and showed intense immunoreactivity. By double immunohistochemical staining, NT3- and TrkC-IR resulted to be colocalized in glucagon immunoreactive cells. These findings suggest endocrine and/or autocrine roles of NT3 in pancreatic A cells. [source] Environmental complexity and central nervous system development and functionDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2004Mark H. Lewis Abstract Environmental restriction or deprivation early in development can induce social, cognitive, affective, and motor abnormalities similar to those associated with autism. Conversely, rearing animals in larger, more complex environments results in enhanced brain structure and function, including increased brain weight, dendritic branching, neurogenesis, gene expression, and improved learning and memory. Moreover, in animal models of CNS insult (e.g., gene deletion), a more complex environment has attenuated or prevented the sequelae of the insult. Of relevance is the prevention of seizures and attenuation of their neuropathological sequelae as a consequence of exposure to a more complex environment. Relatively little attention, however, has been given to the issue of sensitive periods associated with such effects, the relative importance of social versus inanimate stimulation, or the unique contribution of exercise. Our studies have examined the effects of environmental complexity on the development of the restricted, repetitive behavior commonly observed in individuals with autism. In this model, a more complex environment substantially attenuates the development of the spontaneous and persistent stereotypies observed in deer mice reared in standard laboratory cages. Our findings support a sensitive period for such effects and suggest that early enrichment may have persistent neuroprotective effects after the animal is returned to a standard cage environment. Attenuation or prevention of repetitive behavior by environmental complexity was associated with increased neuronal metabolic activity, increased dendritic spine density, and elevated neurotrophin (BDNF) levels in brain regions that are part of cortical,basal ganglia circuitry. These effects were not observed in limbic areas such as the hippocampus. MRDD Research Reviews 2004;10:91,95. © 2004 Wiley-Liss, Inc. [source] Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signalingDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2007Arthur W. English Abstract Electrical stimulation of cut peripheral nerves at the time of their surgical repair results in an enhancement of axon regeneration. Regeneration of axons through nerve allografts was used to evaluate whether this effect is due to an augmentation of cell autonomous neurotrophin signaling in the axons or signaling from neurotrophins produced in the surrounding environment. In the thy-1-YFP-H mouse, a single 1 h application of electrical stimulation at the time of surgical repair of the cut common fibular nerve results in a significant increase in the proportion of YFP+ dorsal root ganglion neurons, which were immunoreactive for BDNF or trkB, as well as an increase in the length of regenerating axons through allografts from wild type litter mates, both 1 and 2 weeks later. Axon growth through allografts from neurotrophin-4/5 knockout mice or grafts made acellular by repeated cycles of freezing and thawing is normally very poor, but electrical stimulation results in a growth of axons through these grafts, which is similar to that observed through grafts from wild type mice after electrical stimulation. When cut nerves in NT-4/5 knockout mice were electrically stimulated, no enhancement of axon regeneration was found. Electrical stimulation thus produces a potent enhancement of the regeneration of axons in cut peripheral nerves, which is independent of neurotrophin production by cells in their surrounding environment but is dependent on stimulation of trkB and its ligands in the regenerating axons themselves. © 2006 Wiley Periodicals, Inc. Develop Neurobiol 67: 158,172, 2007. [source] Developmental changes in the BDNF-induced modulation of inhibitory synaptic transmission in the Kölliker,Fuse nucleus of ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Miriam Kron Abstract The Kölliker,Fuse nucleus (KF), part of the pontine respiratory group, is involved in the control of respiratory phase duration, and receives both excitatory and inhibitory afferent input from various other brain regions. There is evidence for developmental changes in the modulation of excitatory inputs to the KF by the neurotrophin brain-derived neurotrophic factor (BDNF). In the present study we investigated if BDNF exerts developmental effects on inhibitory synaptic transmission in the KF. Recordings of inhibitory postsynaptic currents (IPSCs) in KF neurons in a pontine slice preparation revealed general developmental changes. Recording of spontaneous and evoked IPSCs (sIPSCs, eIPSCS) revealed that neonatally the ,-aminobutyric acid (GABA)ergic fraction of IPSCs was predominant, while in later developmental stages glycinergic neurotransmission significantly increased. Bath-application of BDNF significantly reduced sIPSC frequency in all developmental stages, while BDNF-mediated modulation on eIPSCs showed developmental differences. The eIPSCs mean amplitude was uniformly and significantly reduced following BDNF application only in neurons from rats younger than postnatal day 10. At later postnatal stages the response pattern became heterogeneous, and both augmentations and reductions of eIPSC amplitudes occurred. All BDNF effects on eIPSCs and sIPSCs were reversed with the tyrosine kinase receptor-B inhibitor K252a. We conclude that developmental changes in inhibitory neurotransmission, including the BDNF-mediated modulation of eIPSCs, relate to the postnatal maturation of the KF. The changes in BDNF-mediated modulation of IPSCs in the KF may have strong implications for developmental changes in synaptic plasticity and the adaptation of the breathing pattern to afferent inputs. [source] Neuronal activity and neurotrophic factors regulate GAD-65/67 mRNA and protein expression in organotypic cultures of rat visual cortexEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2003Silke Patz Abstract Environmental factors are known to regulate the molecular differentiation of neocortical interneurons. Their class-defining transmitter synthetic enzymes are the glutamic acid decarboxylases (GAD); yet, fairly little is known about the developmental regulation of transcription and translation of the GAD-65/67 isoforms. We have characterized the role of neuronal activity, neurotrophins and afferent systems for GAD-65/67 expression in visual cortex in organotypic cultures (OTC) compared with in vivo in order to identify cortex-intrinsic regulatory mechanisms. Spontaneously active OTC prepared at postnatal day 0 displayed from 10 days in vitro (DIV) onwards 12,14% GAD-65/GAD-67 neurons similar to in vivo. However, GAD-65 mRNA was higher, whereas GAD-67 protein was lower, than in vivo. During the first week neurotrophins increased whereas the Trk receptor inhibitor K252a and MEK inhibitors decreased both GAD mRNAs and proteins. After 10 DIV GAD expression no longer depended on neurotrophin signalling. Activity-deprived OTC revealed only 6% GAD-67 neurons and mRNA and protein were reduced by 50%. GAD-65 mRNA was less reduced, but protein was reduced by half, suggesting translational regulation. Upon recovery of activity GAD mRNAs, cell numbers, and both proteins quickly returned to normal and these ,adult' levels were resistant to late-onset deprivation. In 20 DIV activity-deprived OTC, only neurotrophin 4 increased GAD-65/67 mRNAs, rescued the percentage of GAD-67 neurons and increased both proteins in a TrkB-dependent manner. Activity deprivation had thus shifted the period of neurotrophin sensitivity to older ages. The results suggested neuronal activity as a major regulator differentially affecting transcription and translation of the GAD isoforms. The early presence of neuronal activity promoted the GAD expression in OTC to a neurotrophin-independent state suggesting that neurotrophins play a context-dependent role. [source] Neuropeptide Y delays hippocampal kindling in the ratHIPPOCAMPUS, Issue 5 2003Sophie Reibel Abstract Chronic intrahippocampal infusion of the neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to delay kindling epileptogenesis in the rat and several lines of evidence suggest that neuropeptide Y could mediate these inhibitory effects. Chronic infusion of BDNF leads to a sustained overexpression of neuropeptide Y in the hippocampus, which follows a time course similar to that of the suppressive effects of BDNF on kindling. In vivo, acute applications of neuropeptide Y or agonists of its receptors exert anticonvulsant properties, especially on seizures of hippocampal origin. In this study, we examined how chronic infusion of this neuropeptide in the hippocampus affected kindling epileptogenesis. A 7-day continuous infusion of neuropeptide Y in the hippocampus delayed the progression of hippocampal kindling in the rat, whereas anti-neuropeptide Y immunoglobulins had an aggravating effect. These results show that neuropeptide Y exerts anti-epileptogenic properties on seizures originating within the hippocampus and lend support to the hypothesis that BDNF delays kindling at least in part through upregulation of this neuropeptide. They also suggest that the seizure-induced upregulation of neuropeptide Y constitutes an endogenous mechanism counteracting excessive hippocampal excitability. Hippocampus 2003;13:557,560. © 2003 Wiley-Liss, Inc. [source] Nerve growth factor blocks thapsigargin-induced apoptosis at the level of the mitochondrion viaregulation of BimJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 6a 2008E. Szegezdi Abstract This study examined how the neurotrophin, nerve growth factor (NGF), protects PC12 cells against endoplasmic reticulum (ER) stress-induced apoptosis. ER stress was induced using thapsigargin (TG) that inhibits the sarcoplasmic/ER Ca2+ -ATPase pump (SERCA) and depletes ER Ca2+ stores. NGF pre-treatment inhibited translocation of Bax to the mitochondria, loss of mitochondrial transmembrane potential, cytochrome c release, activation of caspases (,3, ,7 and ,9) and apoptosis induction by TG. Notably, TG also caused a marked induction of Bimel mRNA and protein, and knockdown of Bim with siRNA protected cells against TG-induced apoptosis. NGF delayed the induction and increased the phosphorylation of Bimel. NGF-mediated protection was dependent on phosphatidylinositol-3 kinase (PI3K) signalling since all above apoptotic events, including expression and phosphorylation status of Bimel protein, could be reverted by the PI3K inhibitor LY294002. In contrast, NGF had no effect on the TG-mediated induction of the unfolded protein response (increased expression of Grp78, GADD34, splicing of XBP1 mRNA) or ER stress-associated pro-apoptotic responses (induction of C/EBP homologous protein [CHOP], induction and processing of caspase-12). These data indicate that NGF-mediated protection against ER stress-induced apoptosis occurs at the level of the mitochondria by regulating induction and activation of Bim and mitochondrial translocation of Bax. [source] Reduced age-related plasticity of neurotrophin receptor expression in selected sympathetic neurons of the ratAGING CELL, Issue 1 2003T. Cowen Summary Selective vulnerability of particular groups of neurons is a characteristic of the aging nervous system. We have studied the role of neurotrophin (NT) signalling in this phenomenon using rat sympathetic (SCG) neurons projecting to cerebral blood vessels (CV) and iris which are, respectively, vulnerable to and protected from atrophic changes during old age. RT-PCR was used to examine NT expression in iris and CV in 3- and 24-month-old rats. NGF and NT3 expression in iris was substantially higher compared to CV; neither target showed any alterations with age. RT-PCR for the principal NT receptors, trkA and p75, in SCG showed increased message during early postnatal life. However, during mature adulthood and old age, trkA expression remained stable while p75 declined significantly over the same period. In situ hybridization was used to examine receptor expression in subpopulations of SCG neurons identified using retrograde tracing. Eighteen to 20 h following local treatment of iris and CV with NGF, NT3 or vehicle, expression of NT receptor protein and mRNA was higher in iris- compared with CV-projecting neurons from both young and old rats. NGF and NT3 treatment had no effect on NT receptor expression in CV-projecting neurons at either age. However, similar treatment up-regulated p75 and trkA expression in iris-projecting neurons from 3-month-old, but not 24-month-old, rats. We conclude that lifelong exposure to low levels of NTs combined with impaired plasticity of NT receptor expression are predictors of neuronal vulnerability to age-related atrophy. [source] The neurotrophic effects of PACAP in PC12 cells: control by multiple transduction pathwaysJOURNAL OF NEUROCHEMISTRY, Issue 2 2006Aurélia Ravni Abstract Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are closely related members of the secretin superfamily of neuropeptides expressed in both the brain and peripheral nervous system, and they exhibit neurotrophic and neurodevelopmental effects in vivo. Like the index member of the Trk receptor ligand family, nerve growth factor (NGF), PACAP promotes the differentiation of PC12 cells, a well-established cell culture model, to investigate neuronal differentiation, survival and function. Stimulation of catecholamine secretion and enhanced neuropeptide biosynthesis are effects exerted by PACAP at the adrenomedullary synapse in vivo and on PC12 cells in vitro through stimulation of the specific PAC1 receptor. Induction of neuritogenesis, growth arrest, and promotion of cell survival are effects of PACAP that occur in developing cerebellar, hippocampal and cortical neurons, as well as in the more tractable PC12 cell model. Study of the mechanisms through which PACAP exerts its various effects on cell growth, morphology, gene expression and survival, i.e. its actions as a neurotrophin, in PC12 cells is the subject of this review. The study of neurotrophic signalling by PACAP in PC12 cells reveals that multiple independent pathways are coordinated in the PACAP response, some activated by classical and some by novel or combinatorial signalling mechanisms. [source] Nerve Growth Factor Secretion in Cultured Enteric Glia Cells is Modulated by Proinflammatory CytokinesJOURNAL OF NEUROENDOCRINOLOGY, Issue 11 2006G. B. T. Von Boyen The enteric nervous system is composed of neurones and glial cells. These enteric glia cells (EGC) appear to be essential for the maintenance of gut homeostasis and mucosal integrity. Neurotrophin nerve growth factor (NGF) also plays an important role for the gut integrity by regulating sensory and inflammatory processes in the intestines. Here, we demonstrate EGCs as one source of NGF and show increased levels of NGF mRNA/protein and tropomyosin receptor kinase A (TrkA) mRNA in cultured EGCs upon stimulation with proinflammatory cytokines and lipopolysaccharides. NGF is continuously secreted from cultured EGCs and proinflammatory cytokines and lipopolysaccharides stimulate the secretion of this neurotrophin in a time- and dose- dependent manner, whereas interleukin-4 had no effect on NGF expression. Furthermore, NGF secretion was sustained for more than 12 h after withdrawal of the proinflammatory cytokines, suggesting the involvement of transcriptional and/or translational processes. Thus, the release of proinflammatory cytokines can increase NGF secretion by EGCs and leads to a higher expression of TrkA in EGCs. NGF, in turn, can increase visceral sensitivity and, on the other hand, appears to improve gut inflammation. Therefore, NGF secreting EGCs may play a key role in modulating visceral sensitivity and might be involved in inflammatory processes of the gut. [source] Interactive roles of fibroblast growth factor 2 and neurotrophin 3 in the sequence of migration, process outgrowth, and axonal differentiation of mouse cochlear ganglion cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2008Waheeda A. Hossain Abstract A growth factor may have different actions depending on developmental stage. We investigated this phenomenon in the interactions of fibroblast growth factor 2 (FGF2) and neurotrophins on cochlear ganglion (CG) development. The portions of the otocyst fated to form the CG and cochlear epithelium were cocultured at embryonic day 11 (E11). Cultures were divided into groups fed with defined medium, with or without FGF2 and neurotrophin supplements, alone or in combination, for 7 days. We measured the number of migrating neuroblasts and distances migrated, neurite outgrowth, and axonlike processes. We used immunohistochemistry to locate neurotrophin 3 (NT3) and its high-affinity receptor (TrkC) in the auditory system, along with FGF2 and its R1 receptor, at comparable developmental stages in vitro and in situ from E11 until birth (P1) in the precursors of hair cells, support cells, and CG cells. Potential sites for interaction were localized to the nucleus, perikaryal cytoplasm, and cell surfaces, including processes and growth cones. Time-lapse imaging and quantitative measures support the hypothesis that FGF2 alone or combined with neurotrophins promotes migration and neurite outgrowth. Synergism or antagonism between NT3 and other factors suggest interactions at the receptor level. Formation of axons, endings, and synaptic vesicle protein 2 were increased by interactions of NT3 and FGF2. Similar experiments with a mutant overexpressor for FGF2 suggest that endogenous FGF2 supports migration and neurite outgrowth of CG neuroblasts as well as proliferation, leading to accelerated development. The findings suggest interactive and sequential roles for FGF2 and NT3. © 2008 Wiley-Liss, Inc. [source] Calcium channel upregulation in response to activation of neurotrophin and surrogate neurotrophin receptor tyrosine kinasesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2003Melony J. Black Abstract Modulation of calcium channel expression and function in the context of neurotrophin induced neuronal differentiation remains incompletely understood at a mechanistic level. We addressed this issue in the PC12 model neuronal system using patch clamp electrophysiology combined with ectopic expression of the human , platelet-derived growth factor (,PDGF) receptor as a surrogate neurotrophin receptor system. PC12 cells ectopically expressing the human ,PDGF receptor were treated with PDGF or nerve growth factor (NGF) for up to 7 days, and Ca2+ channel subtype expression was analyzed using selective pharmacological agents in both whole-cell and cell-attached single channel patch clamp configurations. PDGF-induced upregulation of N- and P/Q-type Ca2+ channel currents completely mimicked upregulation of these currents caused by NGF stimulation of the endogenous TrkA receptor tyrosine kinase (RTK). Neither PDGF nor NGF significantly altered L- or R-type currents. Single channel recordings together with immunocytochemistry implied that growth factor-induced increases in whole-cell Ca2+ currents were a result of synthesis of new channels, and that whereas increased N channel density was apparent in the soma, additional P/Q channels distributed preferentially to extrasomal locations, most likely the proximal neurites. Finally, specific signaling-deficient mutant forms of the ,PDGF receptor were used to show that activation of Src, PI3-kinase, RasGAP, PLC, or SHP-2 (some of which are implicated in certain other aspects of PC12 cell differentiation) by RTKs is not required for growth factor-induced Ca2+ channel upregulation. In contrast, activation of the Ras-related G-protein Rap1 was found critical to this process. © 2003 Wiley-Liss, Inc. [source] Mechanical ventilation with high tidal volume or frequency is associated with increased expression of nerve growth factor and its receptor in rabbit lungsPEDIATRIC PULMONOLOGY, Issue 7 2009Rashmi A. Mittal MD Abstract Objective Nerve growth factor (NGF), a neurotrophin, is induced in lung cells by proinflammatory cytokines, and has a role in bronchial hyperreactivity and lung tissue repair. Ventilation induced lung injury, on the other hand, is known to increase the levels of proinflammatory cytokines in the lungs. We investigated whether, and to what extent, various degrees of lung injury induced by short-term ventilation affect NGF levels in the lung tissue of adolescent rabbits. Methods The rabbits were randomized to different modes of ventilation: (1) CON: normal ventilation for 30,min; (2) NVT: normal ventilation for 6,hr; (3) HFQ: ventilation for 6,hr at double frequency, but normal tidal volume (VT); and (4) HVT: 6,hr ventilation at double VT but normal frequency. Results NGF protein was detected in bronchoalveolar lavage fluid (BALF) and lung tissue in all animals. Ventilation for 6,hr significantly increased NGF levels, in both BALF and lung tissue, in the HFQ and HVT groups as compared to control (P,<,0.05). The maximum increase in BALF NGF was seen in the HVT group (P,=,0.02 vs. CON and NVT groups, and P,=,0.05 vs. HFQ). A parallel increase in interleukin 1-, (IL1-,) was observed. Expression of the high-affinity NGF-receptor, tropomyosin-related kinase A (TrkA), was also upregulated in these two groups. Conclusion Injurious modes of mechanical ventilation upregulate NGF and its receptor TrkA in rabbit lungs, and IL1-beta may be a mediator for this response. We speculate that this increase in NGF level may translate into the development of bronchial hyperreactivity. Pediatr Pulmonol. 2009; 44:713,719. © 2009 Wiley-Liss, Inc. [source] Effects of Castration on the Expression of Neurotrophic Factors in the Vas Deferens and Accessory Genital Glands of the RatANATOMIA, HISTOLOGIA, EMBRYOLOGIA, Issue 2005N. Mirabella Introduction:, Neurotrophic factors constitute a group of growth factor families, which have important effects on survival and differentiation of neuronal cells. The neurotrophin family is composed of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin (NT)3 and NT 4/5. Neurotrophins act by means of high (TrkA, TrkB and TrkC) and low (p75) affinity receptors on numerous neuronal populations of central and peripheral nervous system. The family of glial derived neurotrophic factor (GDNF) includes, besides the GDNF, neurturin (NTN), persephin (PSP) and artemin (ART). They bind to a common receptor Ret, but the binding specificity is due to a group of proteins (GFR, 1,4). These factors show a trophic effect on dorsal ganglia, motor neurons and autonomic nervous system. The aim of the present study is to evaluate the expression of NGF, BDNF and GDNF in the vas deferens and accessory genital glands of normal and castrated rats. Methods:, Immunohistochemistry, enzyme linked immunoassay (ELISA), reverse transcriptase (RT)-polymerase chain reaction (PCR). Results and Discussion:, Immunoreactivity to NGF, BDNF and GDNF was observed in all the investigated tracts. Generally, this immunoreactivity seemed to increase in castrated rats. ELISA and RT-PCR were performed to evaluate the levels of BDNF protein and its mRNA. In the normals, the greatest concentration of BDNF was observed in the vesicular gland, the lowest in the prostate. In the castrated, the BDNF concentration significantly decreased in the vas deferens. Conversely, it increased in the vesicular gland and in the ventral and dorsal prostate. BDNF transcripts were detected in both normal and castrated rats. These results suggest that neurotrophic factors are produced by the vas deferens and accessory genital glands and, in normal conditions, they are downregulated by androgens. [source] C-peptide prevents nociceptive sensory neuropathy in type 1 diabetesANNALS OF NEUROLOGY, Issue 6 2004Hideki Kamiya MD We examined the effects of C-peptide replacement on unmyelinated fiber function in the hind paw, sural nerve C-fiber morphometry, sciatic nerve neurotrophins, and the expression of neurotrophic receptors and content of neuropeptides in dorsal root ganglia in type 1 diabetic BB/Wor-rats. C-peptide replacement from onset of diabetes had no effect on hyperglycemia, but it significantly prevented progressive thermal hyperalgesia and prevented C-fiber atrophy, degeneration, and loss. These findings were associated with preventive effects on impaired availability of nerve growth factor and neurotrophin 3 in the sciatic nerve and significant prevention of perturbed expression of insulin, insulin growth factor,1, nerve growth factor, and neurotrophin 3 receptors in dorsal root ganglion cells. These beneficial effects translated into prevention of the decreased content of dorsal root ganglia nociceptive peptides such as substance P and calcitonin gene,related peptide. From these findings we conclude that replacement of insulinomimetic C-peptide prevents abnormalities of neurotrophins, their receptors, and nociceptive neuropeptides in type 1 BB/Wor-rats, resulting in the prevention of C-fiber pathology and nociceptive sensory nerve dysfunction. The data indicate that perturbed insulin/C-peptide action plays an important pathogenetic role in nociceptive sensory neuropathy and that C-peptide replacement may be of benefit in treating painful diabetic neuropathy in insulin-deficient diabetic conditions. Ann Neurol 2004 [source] BDNF variant linked to anxiety-related behaviorsBIOESSAYS, Issue 2 2007Kenji Hashimoto Brain-derived neurotrophic factor (BDNF) is the most-abundant neurotrophin in the brain. In mammals, it is synthesized as a precursor called proBDNF, which is proteolytically cleaved to generate mature BDNF. The BDNF gene is located on chromosome 11p13, and a functional single nucleotide polymorphism (SNP) of this gene has been shown to produce a valine (Val)-to-methionine (Met) substitution in the proBDNF protein at codon 66 (Val66Met). Several papers suggest that this SNP is related to decreased hippocampal volume and hippocampus-mediated memory performance in humans. Recently, Chen et al.1 generated a variant BDNF mouse (BDNFMet/Met) that reproduces the phenotypic hallmarks in humans with a variant Met allele. In the behavioral analysis, BDNFMet/Met mice show increased anxiety-related behaviors. This mini-review examines the impact of Met substitution of proBDNF on anxiety-related behaviors. BioEssays 29: 116,119, 2007. © 2007 Wiley Periodicals, Inc. [source] Sustained MAPK activation is dependent on continual NGF receptor regenerationDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 5 2004Dongru Qiu It still remains intriguing how signal specificity is achieved when different signals are relayed by the common intracellular signal transduction pathways. A well documented example for signal specificity determination is found in rat phaeochromocytoma PC12 cells where epidermal growth factor (EGF) stimulation produces a transient mitogen-activated protein kinase (MAPK) activation and leads to cell proliferation while nerve growth factor (NGF) initiates a sustained MAPK activation and induces cell differentiation. In this simulation, we demonstrated that NGF-induced sustained MAPK activation may mainly depend on continual regeneration of NGF receptors and that the presence of a small pool of surface receptors is enough to maintain a sustained MAPK activation. On the other hand, MAPK activation is not significantly sensitive to the half-life of internalized receptors and the levels of NGF-specific MAPK phosphatase MAP kinase phosphatase-3 (MKP-3), though cytoplasmic persistence of internalized NGF-bound receptors and the MKP-3 dependent feedback control also contribute to the sustaining of MAPK activation. These results are consistent with the recent experimental evidence that persistent tyrosine receptor kinase A (TrkA) activity is necessary to maintain transcription in the differentiating PC12 cells (Chang et al. 2003) and a sustained Src kinase activity is detected in response to NGF stimulation (Gatti 2003). It is suggested that sustained or transient MAPK activation induced by different growth factor and neurotrophins, which is crucial to their signaling specificity, could be satisfactorily accounted for by their specific receptor turnover kinetics rather than by the activation of specific downstream signaling cascades. [source] Brain-derived neurotrophic factor and the development of structural neuronal connectivityDEVELOPMENTAL NEUROBIOLOGY, Issue 5 2010Susana Cohen-Cory Abstract During development, neural networks are established in a highly organized manner, which persists throughout life. Neurotrophins play crucial roles in the developing nervous system. Among the neurotrophins, brain-derived neurotrophic factor (BDNF) is highly conserved in gene structure and function during vertebrate evolution, and serves an important role during brain development and in synaptic plasticity. BDNF participates in the formation of appropriate synaptic connections in the brain, and disruptions in this process contribute to disorders of cognitive function. In this review, we first briefly highlight current knowledge on the expression, regulation, and secretion of BDNF. Further, we provide an overview of the possible actions of BDNF in the development of neural circuits, with an emphasis on presynaptic actions of BDNF during the structural development of central neurons. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 2010 [source] Electrical stimulation promotes peripheral axon regeneration by enhanced neuronal neurotrophin signalingDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2007Arthur W. English Abstract Electrical stimulation of cut peripheral nerves at the time of their surgical repair results in an enhancement of axon regeneration. Regeneration of axons through nerve allografts was used to evaluate whether this effect is due to an augmentation of cell autonomous neurotrophin signaling in the axons or signaling from neurotrophins produced in the surrounding environment. In the thy-1-YFP-H mouse, a single 1 h application of electrical stimulation at the time of surgical repair of the cut common fibular nerve results in a significant increase in the proportion of YFP+ dorsal root ganglion neurons, which were immunoreactive for BDNF or trkB, as well as an increase in the length of regenerating axons through allografts from wild type litter mates, both 1 and 2 weeks later. Axon growth through allografts from neurotrophin-4/5 knockout mice or grafts made acellular by repeated cycles of freezing and thawing is normally very poor, but electrical stimulation results in a growth of axons through these grafts, which is similar to that observed through grafts from wild type mice after electrical stimulation. When cut nerves in NT-4/5 knockout mice were electrically stimulated, no enhancement of axon regeneration was found. Electrical stimulation thus produces a potent enhancement of the regeneration of axons in cut peripheral nerves, which is independent of neurotrophin production by cells in their surrounding environment but is dependent on stimulation of trkB and its ligands in the regenerating axons themselves. © 2006 Wiley Periodicals, Inc. Develop Neurobiol 67: 158,172, 2007. [source] Dose and age-dependent axonal responses of embryonic trigeminal neurons to localized NGF via p75NTR receptorDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2005P. Hande Özdinler Abstract Nerve growth factor (NGF) and related neurotrophins are target-derived survival factors for sensory neurons. In addition, these peptides modulate neuronal differentiation, axon guidance, and synaptic plasticity. We tested axonal behavior of embryonic trigeminal neurons towards localized sources of NGF in collagen gel assays. Trigeminal axons preferentially grow towards lower doses of localized NGF and grow away from higher concentrations at earlier stages of development, but do not show this response later. Dorsal root ganglion axons also show similar responses to NGF, but NGF-dependent superior cervical ganglion axons do not. Such axonal responses to localized NGF sources were also observed in Bax,/, mice, suggesting that the axonal effects are largely independent of cell survival. Immunocytochemical studies indicated that axons, which grow towards or away from localized NGF are TrkA-positive, and TrkA,/, TG axons do not respond to any dose of NGF. We further show that axonal responses to NGF are absent in TG derived from mice that lack the p75 neurotrophin receptor (p75NTR). Collectively, our results suggest that localized sources of NGF can direct axon outgrowth from trigeminal ganglion in a dose- and age-dependent fashion, mediated by p75NTR signaling through TrkA expressing axons. © 2004 Wiley Periodicals, Inc. J Neurobiol, 2005 [source] High-resolution imaging demonstrates dynein-based vesicular transport of activated trk receptorsDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2002Anita Bhattacharyya Abstract Target-derived neurotrophins signal from nerve endings to the cell body to influence cellular and nuclear responses. The retrograde signal is conveyed by neurotrophin receptors (Trks) themselves. To accomplish this, activated Trks may physically relocalize from nerve endings to the cell bodies. However, alternative signaling mechanisms may also be used. To identify the vehicle wherein the activated Trks are located and transported, and to identify associated motor proteins that would facilitate transport, we use activation-state specific antibodies in concert with immunoelectron microscopy and deconvolution microscopy. We show that the activated Trks within rat sciatic nerve axons are preferentially localized to coated and uncoated vesicles. These vesicles are moving in a retrograde direction and so accumulate distal to a ligation site. The P-Trk containing vesicles, in turn, colocalize with dynein components, and not with kinesins. Collectively, these results indicate activated Trk within axons travel in vesicles and dynein is the motor that drives these vesicles towards the cell bodies. © 2002 Wiley Periodicals, Inc. J Neurobiol 51: 302,312, 2002 [source] Role of macrophage activation in the pathogenesis of Alzheimer's disease and human immunodeficiency virus type 1-associated dementiaEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2000Smits The structure and function of neurons are changed not only during development of the central nervous system but also in certain neurological disorders, such as Alzheimer's disease and human immunodeficiency virus type 1 (HIV-1) -associated dementia. Immunological activation and altered production of neurotoxins and neurotrophins by brain macrophages are thought to play an important role in neuronal structure and function. This review describes the clinical and pathological features of both Alzheimer's disease and HIV-1-associated dementia and tries to interpret the role of the macrophage and astrocytes therein. The consequences of activation of macrophages by amyloid-, in Alzheimer's disease and HIV infection of macrophages in HIV-1-associated dementia and the similarities between these diseases will be discussed. Although the neuropathology of Alzheimer's disease and HIV-1-associated dementia differs, Alzheimer's disease is a cortical dementia and HIV-1-associated dementia is a subcortical dementia, the process of macrophage activation and the resulting pathways leading to neurotoxicity seem very similar. In both Alzheimer's disease and HIV-1-associated dementia, interaction of macrophages and astrocytes appear to play an important role. [source] CLINICAL STUDY: BRIEF REPORT: Ecstasy (MDMA)-addicted subjects show increased serum levels of brain-derived neurotrophic factor, independently from a rise of drug-induced psychotic symptomsADDICTION BIOLOGY, Issue 3 2010Francesco Angelucci ABSTRACT The recreational drug ,ecstasy'[3,4-methylenedioxymethamphetamine (MDMA)] exerts a potent action on central serotonergic and dopaminergic neurons. These neurons utilize neurotrophins for their survival and function. In order to explore MDMA effects on neurotrophins, we measured by enzyme-linked immunosorbent assay the serum levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in ,ecstasy-addicted', ,ecstasy-addicted with signs of psychosis' and ,healthy' subjects. We found that BDNF serum levels were significantly increased in both groups of ,ecstasy-addicted' as compared with ,healthy subjects', supporting the hypothesis that BDNF is involved in MDMA action. [source] Effect of neurotrophin-3 on reinnervation of the larynx using the phrenic nerve transfer techniqueEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2007Paul J. Kingham Abstract Current techniques for reinnervation of the larynx following recurrent laryngeal nerve (RLN) injury are limited by synkinesis, which prevents functional recovery. Treatment with neurotrophins (NT) may enhance nerve regeneration and encourage more accurate reinnervation. This study presents the results of using the phrenic nerve transfer method, combined with NT-3 treatment, to selectively reinnervate the posterior cricoarytenoid (PCA) abductor muscle in a pig nerve injury model. RLN transection altered the phenotype and morphology of laryngeal muscles. In both the PCA and thyroarytenoid (TA) adductor muscle, fast type myosin heavy chain (MyHC) protein was decreased while slow type MyHC was increased. These changes were accompanied with a significant reduction in muscle fibre diameter. Following nerve repair there was a progressive normalization of MyHC phenotype and increased muscle fibre diameter in the PCA but not the TA muscle. This correlated with enhanced abductor function indicating the phrenic nerve accurately reinnervated the PCA muscle. Treatment with NT-3 significantly enhanced phrenic nerve regeneration but led to only a small increase in the number of reinnervated PCA muscle fibres and minimal effect on abductor muscle phenotype and morphology. Therefore, work exploring other growth factors, either alone or in combination with NT-3, is required. [source] Neuronal activity and neurotrophic factors regulate GAD-65/67 mRNA and protein expression in organotypic cultures of rat visual cortexEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2003Silke Patz Abstract Environmental factors are known to regulate the molecular differentiation of neocortical interneurons. Their class-defining transmitter synthetic enzymes are the glutamic acid decarboxylases (GAD); yet, fairly little is known about the developmental regulation of transcription and translation of the GAD-65/67 isoforms. We have characterized the role of neuronal activity, neurotrophins and afferent systems for GAD-65/67 expression in visual cortex in organotypic cultures (OTC) compared with in vivo in order to identify cortex-intrinsic regulatory mechanisms. Spontaneously active OTC prepared at postnatal day 0 displayed from 10 days in vitro (DIV) onwards 12,14% GAD-65/GAD-67 neurons similar to in vivo. However, GAD-65 mRNA was higher, whereas GAD-67 protein was lower, than in vivo. During the first week neurotrophins increased whereas the Trk receptor inhibitor K252a and MEK inhibitors decreased both GAD mRNAs and proteins. After 10 DIV GAD expression no longer depended on neurotrophin signalling. Activity-deprived OTC revealed only 6% GAD-67 neurons and mRNA and protein were reduced by 50%. GAD-65 mRNA was less reduced, but protein was reduced by half, suggesting translational regulation. Upon recovery of activity GAD mRNAs, cell numbers, and both proteins quickly returned to normal and these ,adult' levels were resistant to late-onset deprivation. In 20 DIV activity-deprived OTC, only neurotrophin 4 increased GAD-65/67 mRNAs, rescued the percentage of GAD-67 neurons and increased both proteins in a TrkB-dependent manner. Activity deprivation had thus shifted the period of neurotrophin sensitivity to older ages. The results suggested neuronal activity as a major regulator differentially affecting transcription and translation of the GAD isoforms. The early presence of neuronal activity promoted the GAD expression in OTC to a neurotrophin-independent state suggesting that neurotrophins play a context-dependent role. [source] Connecting the dots: trafficking of neurotrophins, lectins and diverse pathogens by binding to the neurotrophin receptor p75NTREUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2003Rafal Butowt Abstract The common receptor for neurotrophins, p75, has important roles in internalization and trafficking of neurotrophins along axons. Recent studies show that an astonishing array of proteins, including lectins, pathogens and neurotoxins, bind the p75 receptor, suggesting that they can hijack and utilize this receptor for trafficking between neuronal populations within the nervous system. Such pathogens include the neurologically important rabies viruses, prion proteins, ,-amyloid and possibly tetanus toxin. These proteins may hijack existing transport machineries designed to traffick neurotrophins, thus allowing the infiltration and distribution of pathogens and toxins among vulnerable neuronal populations with devastating effects, as seen in rabies, prion encephalopathies, Alzheimer's disease and tetanic muscle spasm. The discovery of an entry and transport machinery that is potentially shared between pathogens and neurotrophins sheds light ono trafficking systems in the nervous system and may assist the design of novel therapeutic avenues that prevent or slow the progression of diverse chronic and acute neurological disorders. [source] Excess target-derived neurotrophin-3 alters the segmental innervation of the skinEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2001Amy M. Ritter Abstract It is thought that dermatomes are established during development as a result of competition between afferents of neighbouring segments. Mice that overexpress neurotrophins in the skin provide an interesting model to test this hypothesis, as they possess increased numbers of sensory neurons, and display hyperinnervation of the skin. When dermatomal boundaries were mapped in adult mice, it was found that those in nerve growth factor and brain-derived neurotrophic factor overexpressers were indistinguishable from wild-type animals but that overlap between adjacent segments was greatly reduced in neurotrophin-3 (NT-3) overexpressers. However, dermatomes in heterozygous NT-3 knockout mice displayed no more overlap than wild-types. In order to quantify differences across strains, innervation territories of thoracic dorsal cutaneous nerves were mapped and measured in adult mice. Overlap between adjacent dorsal cutaneous nerves was normal in nerve growth factor overexpressing mice, but much reduced in NT-3 overexpressers. However, this restriction was not reflected in the central projection of the dorsal cutaneous nerve, creating a mismatch between peripheral and central projections. Dorsal cutaneous nerve territories were also mapped in neonatal mice aged postnatal day 7,8. In neonates, nerve territories of NT-3 overexpressers overlapped less than wild-types, but in neonates of both strains the amount of overlap was much greater than in the adult. These results indicate that substantial separation of dermatomes occurs postnatally, and that excess NT-3 enhances this process, resulting in more restricted dermatomes. It may exert its effects either by enhancing competition, or by direct effects on the stability and formation of sensory endings in the skin. [source] BDNF, NT-3 and NGF induce distinct new Ca2+ channel synthesis in developing hippocampal neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000Pietro Baldelli Abstract Neurotrophins exert short- and long-term effects on synaptic transmission. The mechanism underlying these forms of synaptic plasticity is unknown although it is likely that intracellular Ca2+ and presynaptic Ca2+ channels play a critical role. Here we show that BDNF, NGF and NT-3 (10,100 ng/mL) exhibit a selective long-term up-regulation of voltage-gated Ca2+ current densities in developing hippocampal neurons of 6,20 days in culture. NGF and NT-3 appear more effective in up-regulating L-currents, while BDNF predominantly acts on non-L-currents (N, P/Q and R). The effects of the three neurotrophins were time- and dose-dependent. The EC50 was comparable for BDNF, NGF and NT-3 (10,16 ng/mL) while the time of half-maximal activation was significantly longer for NGF compared to BDNF (58 vs. 25 h). Despite the increased Ca2+ current density, the neurotrophins did not alter the voltage-dependence of channel activation, the kinetics parameters or the elementary properties of Ca2+ channels (single-channel conductance, probability of opening and mean open time). Neurotrophin effects were completely abolished by coincubation with the nonspecific Trk-receptor inhibitor K252a, the protein synthesis blocker anisomycin and the MAP-kinase inhibitor PD98059, while cotreatment with the PLC-, blocker, U73122, was without effect. Immunocytochemistry and Western blotting revealed that neurotrophins induced an increased MAP-kinase phosphorylation and its translocation to the nucleus. The present findings suggest that on a long time scale different neurotrophins can selectively up-regulate different Ca2+ channels. The action is mediated by Trk-receptors/MAP-kinase pathways and induces an increased density of newly available Ca2+ channels with unaltered gating activity. [source] Expression of c-Met in developing rat hippocampus: evidence for HGF as a neurotrophic factor for calbindin D-expressing neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2000Laura Korhonen Abstract Hepatocyte growth factor-scatter factor (HGF) is expressed in different parts of the nervous system, and has been shown to exhibit neurotrophic activity. Here we show that c-Met, the receptor for HGF, is expressed in developing rat hippocampus, with the highest levels during the first postnatal weeks. To study the function of HGF, hippocampal neurons were prepared from embryonic rats and treated with different HGF concentrations. In these cultures, HGF increased the number of neurons expressing the 28-kDa calcium-binding protein (calbindin D) in a dose-dependent manner. The effect of HGF was larger than that observed with either brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), and cotreatment of the cultures with HGF and the neurotrophins was additive with respect to calbindin D neurons. Besides affecting the number of neurons, HGF significantly increased the degree of sprouting of calbindin D-positive neurons, suggesting an influence on neuronal maturation. BDNF and NT-3 stimulated neurite outgrowth of calbindin D neurons to a much smaller degree. In contrast to calbindin D neurons, HGF did not significantly increase the number of neurons immunoreactive with the neurotransmitter ,-aminobutyric acid (GABA) in the hippocampal cultures. Immunohistochemical studies showed that c-Met-, calbindin D- and HGF-immunoreactive cells are all present in the dentate gyrus and partly colocalize within neurons. These results show that HGF acts on calbindin D-containing hippocampal neurons and increases their neurite outgrowth, suggesting that HGF plays an important role for the maturation and function of these neurons in the hippocampus. [source] Deafferentation-induced apoptosis of neurons in thalamic somatosensory nuclei of the newborn rat: critical period and rescue from cell death by peripherally applied neurotrophinsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2000Alfonso Baldi Abstract This study shows that unilateral transection of the infraorbital nerve (ION) in newborn (P0) rats induces apoptosis in the contralateral ventrobasal thalamic (VB) complex, as evidenced by terminal transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) and electron miscroscopy. Double-labelling experiments using retrograde transport of labelled microspheres injected into the barrel cortex, followed by TUNEL staining, show that TUNEL-positive cells are thalamocortical neurons. The number of TUNEL-positive cells had begun to increase by 24 h postlesion, increased further 48 h after nerve section, and decreased to control levels after 120 h. Lesion-induced apoptosis in the VB complex is less pronounced if ION section is performed at P4, and disappears if the lesion is performed at P7. This time course closely matches the critical period of lesion-induced plasticity in the barrel cortex. Nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF), applied on the ION stump alone or in combination, are able to partially rescue thalamic neurons from apoptosis. Total cell counts in the VB complex of P7 animals that underwent ION section at P0 confirm the rescuing effect of BDNF and NGF. Blockade of axonal transport in the ION mimics the effect of ION section. These data suggest that survival-promoting signals from the periphery, maybe neurotrophins, are required for the survival of higher-order neurons in the somatosensory system during the period of fine-tuning of neuronal connections. We also propose that anterograde transneuronal degeneration in the neonatal rat trigeminal system may represent a new animal model for studying the pathways of programmed cell death in vivo. [source] |