1,721,087 research outputs found
Chemical LTP induces confinement of BDNF mRNA under dendritic spines and BDNF protein accumulation inside the spines
Full text linkThe neurotrophin brain-derived neurotrophic factor (BDNF) plays a key role in neuronal development and synaptic plasticity. The discovery that BDNF mRNA can be transported in neuronal dendrites in an activity-dependent manner has suggested that its local translation may support synapse maturation and plasticity. However, a clear demonstration that BDNF mRNA is locally transported and translated at activated synapses in response to long-term potentiation (LTP) is still lacking. Here, we study the dynamics of BDNF mRNA dendritic trafficking following the induction of chemical LTP (cLTP). Dendritic transport of BDNF transcripts was analyzed using the MS2 system for mRNA visualization, and chimeric BDNF-GFP constructs were used to monitor protein synthesis in living neurons. We found that within 15 min from cLTP induction, most BDNF mRNA granules become stationary and transiently accumulate in the dendritic shaft at the base of the dendritic spines, while at 30 min they accumulate inside the spine, similar to the control CamkIIα mRNA which also increased inside the spines at 60 min post-cLTP. At 60 min but not at 15 min from cLTP induction, we observed an increase in BDNF protein levels within the spines. Taken together, these findings suggest that BDNF mRNA trafficking is arrested in the early phase of cLTP, providing a local source of mRNA for BDNF translation at the base of the spine followed by translocation of both the BDNF mRNA and protein within the spine head in the late phase of LTP
Distinct role of 5′UTR sequences in dendritic trafficking of BDNF mRNA: additional mechanisms for the BDNF splice variants spatial code
Full text linkThe neurotrophin Brain-derived neurotrophic factor (BDNF) is encoded by multiple bipartite transcripts. Each BDNF transcript is composed by one out of 11 alternatively spliced exons containing the 5′untranslated region (UTR), and one common exon encompassing the coding sequence (CDS) and the 3′UTR with two variants (short and long). In neurons, BDNF mRNA variants have a distinct subcellular distribution, constituting a “spatial code”, with exon 1, 3, 5, 7 and 8 located in neuronal somata, exon 4 extending into proximal dendrites, and exon 2 and 6 reaching distal dendrites. We previously showed that the CDS encodes constitutive dendritic targeting signals (DTS) and that both the 3′UTR-short and the 3′UTR-long contain activity-dependent DTS. However, the role of individual 5′UTR exons in mRNA sorting remains unclear. Here, we tested the ability of each different BDNF 5′UTRs to affect the subcellular localization of the green fluorescent protein (GFP) reporter mRNA. We found that exon 2 splicing isoforms (2a, 2b, and 2c) induced a constitutive dendritic targeting of the GFP reporter mRNA towards distal dendritic segments. The other isoforms did not affect GFP-mRNA dendritic trafficking. Through a bioinformatic analysis, we identified five unique cis-elements in exon 2a, 2b, and 2c which might contribute to building a DTS. This study provides additional information on the mechanism regulating the cellular sorting of BDNF mRNA variants
Accumulation of BDNF in the dendrites: a link with epileptogenesis?
No full textThe dendritic targeting of mRNAs and their local protein synthesis are mechanisms that enable neurons to deliver proteins to specific postsynaptic sites. BDNF mRNA is one example of mRNA that accumulates in the dendrites in an activity-dependent manner. Epileptogenic stimuli, via NMDA receptor activation, can induce a dramatic accumulation of BDNF mRNA and protein in discrete dendritic laminae of hippocampal neurons in vivo, suggesting targeting to synapses that are active during seizures. Based on the synaptic effects of BDNF, i.e. potentiation of active excitatory synapses, we propose that this phenomenon may play a critical role in the cellular changes leading to epilepsy. In keeping with this idea, a human BDNF polimorfism leading to increased translatability of BDNF in the dendrites is associated with partial epilepsy. However, further studies era required to conclusively establish if indeed a causal relationship exists between the accumulation of BDNF in dendrites and epileptogenesis
Amyloid-β Impairs Dendritic Trafficking of Golgi-Like Organelles in the Early Phase Preceding Neurite Atrophy: Rescue by Mirtazapine
Full text linkNeurite atrophy with loss of neuronal polarity is a pathological hallmark of Alzheimer’s disease (AD) and other neurological disorders. While there is substantial agreement that disruption of intracellular vesicle trafficking is associated with axonal pathology in AD, comparatively less is known regarding its role in dendritic atrophy. This is a significant gap of knowledge because, unlike axons, dendrites are endowed with the complete endomembrane system comprising endoplasmic reticulum (ER), ER–Golgi intermediate compartment (ERGIC), Golgi apparatus, post-Golgi vesicles, and a recycling-degradative route. In this study, using live-imaging of pGOLT-expressing vesicles, indicative of Golgi outposts and satellites, we investigate how amyloid-β (Aβ) oligomers affect the trafficking of Golgi-like organelles in the different dendritic compartments of cultured rat hippocampal neurons. We found that short-term (4 h) treatment with Aβ led to a decrease in anterograde trafficking of Golgi vesicles in dendrites of both resting and stimulated (with 50 mM KCl) neurons. We also characterized the ability of mirtazapine, a noradrenergic and specific serotonergic tetracyclic antidepressant (NaSSA), to rescue Golgi dynamics in dendrites. Mirtazapine treatment (10 μM) increased the number and both anterograde and retrograde motility, reducing the percentage of static Golgi vesicles. Finally, mirtazapine reverted the neurite atrophy induced by 24 h treatment with Aβ oligomers, suggesting that this drug is able to counteract the effects of Aβ by improving the dendritic trafficking of Golgi-related vesicles
Matrici classiche e italiane nella produzione italofona dei poeti brasiliani contemporanei in esilio in Italia.
Full text linkDopo un iniziale censimento dei poeti migranti operanti in Italia, la ricerca evidenzia la centralità della produzione dei poeti di origine brasiliana all'interno della letteratura della migrazione in lingua italiana e la sua concomitanza con la coeva produzione poetica dell'esilio. Essa sottolinea la centralità di fattori - poi definiti funzioni- quali la produzione del lustro brasiliano di Giuseppe Ungaretti e la riflessione stanziale di argomento meridionalista degli anni Cinquanta. Tali funzioni appaiono centrali nella riflessione dei poeti contemporanei italofoni di origini brasiliane, caratterizzata da una approfondita e costante ricerca intorno alle strutture linguistiche proprie dell'attraversamento interlinguistico ed a riflessioni sulla valenza del dato somatico nella significazione del passaggio verso la patria d'elezion
Brain-derived neurotrophic factor (BDNF) induces dendritic targeting of BDNF and tyrosine kinase B mRNAs in hippocampal neurons through a phosphatidylinositol-3 kinase-dependent pathway
No full textThis study aims to understand the mechanisms of dendritic targeting of brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) mRNAs. We show that brief depolarizations are sufficient to induce accumulation of BDNF and TrkB mRNAs in dendrites of hippocampal neurons. Endogenous BDNF, secreted during the KCl stimulation, contributes significantly to the dendritic accumulation of BDNF-TrkB mRNAs. In the absence of depolarization, 1 min pulses of exogenous BDNF are sufficient to induce dendritic accumulation of BDNF-TrkB mRNAs. After binding to TrkB, BDNF exerts this action by activating a PI-3 kinase-dependent pathway. The accumulation of dendritic mRNA by BDNF is not mediated by BDNF-induced neurotransmitter release. Because most hippocampal neurons coexpress BDNF and TrkB receptors, these results show that the subcellular distribution of BDNF-TrkB mRNAs is under the control of an autocrine-paracrine BDNF-TrkB-dependent loop
Activity-dependent dendritic targeting of BDNF and TrkB mRNAs in hippocampal neurons
No full textThe mechanisms underlying the subcellular localization of neurotrophins and their receptors are poorly understood. We show that in cultured hippocampal neurons, the mRNAs for BDNF and TrkB have a somatodendritic localization, and we quantify the extent of their dendritic mRNA localization. In the dendrites the labeling covers on average the proximal 30% of the total dendritic length. On high potassium depolarization, the labeling of BDNF and TrkB mRNA extends on average to 68% of the dendritic length. This increase does not depend on new RNA synthesis, is inhibited by the Na+ channel blocker tetrodotoxin, and involves the activation of glutamate receptors. Extracellular Ca2+, partly flowing through L-type Ca2+ channels, is absolutely required for this process to occur. At the protein level, a brief stimulation of hippocampal neurons with 10 mM KCl leads to a marked increase of BDNF and TrkB immunofluorescence density in the distal portion of dendrites, which also occurs, even if at lower levels, when transport is inhibited by nocodazole. The protein synthesis inhibitor cycloheximide abolishes this increase. The activity-dependent modulation of mRNA targeting and protein accumulation in the dendrites may provide a mechanism for achieving a selective local regulation of the activity of neurotrophins and their receptors, close to their sites of action
Angels and demons: neurotrophic factors and epilepsy
No full textSeveral lines of evidence indicate that neurotrophic factors (NTFs) could be key causal mediators in the development of acquired epileptic syndromes. At the same time, the trophic properties of NTFs suggest that they may be used for the treatment of epilepsy-associated damage. Accordingly, different NTFs, or even the very same NTF, may produce functionally contrasting effects in the context of epilepsy. Recent experimental evidence begins to shed light on the mechanisms underlying these contrasting effects. Understanding these mechanisms will be instrumental for the development of effective therapies that must be based on a careful consideration of the biological properties of NTFs. This review aims at critically evaluating new information emerging in this area and at discussing its implications in the prospect of clinical applications
Co-expression of TrkB and the N-methyl-D-aspartate receptor subunits NR1-C1, NR2A and NR2B in the rat visual cortex
No full textIn the visual cortex, brain-derived neurotrophic factor expression is modulated through glutamate receptors, including the N-methyl-D-aspartate glutamate receptor. It has been proposed that the N-methyl-D-aspartate glutamate receptor subunit composition itself might be regulated by brain-derived neurotrophic factor. Here, we investigated the co-expression of the neurotrophin-4/brain-derived neurotrophic factor receptor TrkB with the N-methyl-D-aspartate glutamate receptor subunits NR1-C1, NR2A and NR2B, on postnatal days 10 and 22 and in the adult rat primary visual cortex. At both postnatal days 10 and 22, TrkB is co-expressed in all cortical layers with the studied N-methyl-D-aspartate glutamate receptor subunits. In the adult, in layers IV-V, co-expression is restricted to a subpopulation of neurons, while in layers II-III, VI nearly all neurons co-express TrkB with NR1-C1, NR2A and NR2B. We conclude that in layers IV-V, the co-expression of TrkB with subunits NR2B and NR2A is developmentally regulate
Co-expression of TrkB and the N-methyl-D-aspartate receptor subunits NR1-C1, NR2A and NR2B in the rat visual cortex
No full textIn the visual cortex, brain-derived neurotrophic factor expression is modulated through glutamate receptors, including the N-methyl-D-aspartate glutamate receptor. It has been proposed that the N-methyl-D-aspartate glutamate receptor subunit composition itself might be regulated by brain-derived neurotrophic factor. Here, we investigated the co-expression of the neurotrophin-4/brain-derived neurotrophic factor receptor TrkB with the N-methyl-D-aspartate glutamate receptor subunits NR1-C1, NR2A and NR2B, on postnatal days 10 and 22 and in the adult rat primary visual cortex. At both postnatal days 10 and 22, TrkB is co-expressed in all cortical layers with the studied N-methyl-D-aspartate glutamate receptor subunits. In the adult, in layers IV-V, co-expression is restricted to a subpopulation of neurons, while in layers II-III, VI nearly all neurons co-express TrkB with NR1-C1, NR2A and NR2B. We conclude that in layers IV-V, the co-expression of TrkB with subunits NR2B and NR2A is developmentally regulated. (C) 1999 IBRO. Published by Elsevier Science Ltd
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