Ji Y, Lu Y, Yang F, Shen W, Tang TT, Feng L et al. Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons. Nat Neurosci 13: 302-309

Section on Neural Development and Plasticity, National Institute of Child Health and Human Development, Bethesda, Maryland, USA.
Nature Neuroscience (Impact Factor: 16.1). 02/2010; 13(3):302-9. DOI: 10.1038/nn.2505
Source: PubMed


Extracellular factors may act on cells in two distinct modes: an acute increase in concentration as a result of regulated secretion, or a gradual increase in concentration when secreted constitutively or from a distant source. We found that cellular responses to brain-derived neurotrophic factor (BDNF) differed markedly depending on how BDNF was delivered. In cultured rat hippocampal neurons, acute and gradual increases in BDNF elicited transient and sustained activation of TrkB receptor and its downstream signaling, respectively, leading to differential expression of Homer1 and Arc. Transient TrkB activation promoted neurite elongation and spine head enlargement, whereas sustained TrkB activation facilitated neurite branch and spine neck elongation. In hippocampal slices, fast and slow increases in BDNF enhanced basal synaptic transmission and LTP, respectively. Thus, the kinetics of TrkB activation is critical for cell signaling and functions. This temporal dimension in cellular signaling may also have implications for the therapeutic drug design.

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    • "Dendrites and spines were traced and marked manually in a three-dimensional space. The loss or gain rate of dendritic spines was calculated as the percentage of spines that appeared or disappeared on day 1, relative to the total number of spines on day 0. The length of spines was measured from the tip of the spine to the interface with the dendritic stalk (Ji et al., 2010 "
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    ABSTRACT: Two-photon microscopy in combination with a technique involving the artificial expression of fluorescent protein has enabled the direct observation of dendritic spines in living brains. However, the application of this method to primate brains has been hindered by the lack of appropriate labeling techniques for visualizing dendritic spines. Here, we developed an adeno-associated virus vector-based fluorescent protein expression system for visualizing dendritic spines in vivo in the marmoset neocortex. For the clear visualization of each spine, the expression of reporter fluorescent protein should be both sparse and strong. To fulfill these requirements, we amplified fluorescent signals using the tetracycline transactivator (tTA)-tetracycline-responsive element system and by titrating down the amount of Thy1S promoter-driven tTA for sparse expression. By this method, we were able to visualize dendritic spines in the marmoset cortex by two-photon microscopy in vivo and analyze the turnover of spines in the prefrontal cortex. Our results demonstrated that short spines in the marmoset cortex tend to change more frequently than long spines. The comparison of in vivo samples with fixed samples showed that we did not detect all existing spines by our method. Although we found glial cell proliferation, the damage of tissues caused by window construction was relatively small, judging from the comparison of spine length between samples with or without window construction. Our new labeling technique for two-photon imaging to visualize in vivo dendritic spines of the marmoset neocortex can be applicable to examining circuit reorganization and synaptic plasticity in primates.
    08/2015; 2(4). DOI:10.1523/ENEURO.0019-15.2015
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    • "BDNF enhances the expression and trafficking of GluN2A in cultured cortical and hippocampal neurons, and induces the phosphorylation of GluN2A subunit in PSD of rat spinal cord (Di et al., 2001; Hayashi et al., 2000), which is associated with an increase in NMDA receptor activity (Caldeira et al., 2007b; Small et al., 1998), whereas absence of BDNF induces a reduction of GluN2A level in the visual cortex of BDNF knock-out mice (Margottil and Domenici, 2003). Involvement of GluN2A-containing NMDA (GluN2A-NMDA) receptor in the development of LTP is supported by the findings that pharmacological inhibition of GluN2A by NVP-AAM077 blocks the induction of LTP in multiple brain regions including the hippocampus (Bartlett et al., 2007; Fox et al., 2006; Jin and Feig, 2010; Li et al., 2007; Liu et al., 2004; Volianskis et al., 2013), the cortex (Massey et al., 2004) as well as the amygdala (Dalton et al., 2012; Muller et al., 2009) and the nucleus accumbens (Schotanus and Chergui, 2008). Deletion of GluN2A subunit in mice results in a impaired induction of postsynaptic LTP in the dentate gyrus (Kannangara et al., 2014) and the visual cortex (Philpot et al., 2007), and at the mossy fiber to granule cell synapse in the cerebellum (Andreescu et al., 2011). "
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    ABSTRACT: The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. Second, we revealed that BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B-NMDA receptors in the spinal dorsal horn, and this BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high-frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Disease 11/2014; 73C:428-451. DOI:10.1016/j.nbd.2014.10.025 · 5.08 Impact Factor
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    • "Age-related changes in the expression of genes related to synaptic plasticity may contribute to memory decline and vulnerability to cognitive diseases. For instance, brain-derived neurotrophic factor (BDNF) is involved in mechanisms of longterm potentiation (LTP), a major form of synaptic plasticity (Figurov et al., 1996; Ji et al., 2010). BDNF is downregulated with age in rat hippocampus, and its depletion is associated with a decline in synaptic plasticity (Zeng et al., 2011). "
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    ABSTRACT: Advancing age is associated with the loss of cognitive ability and vulnerability to debilitating mental diseases. Although much is known about the development of cognitive processes in the brain, the study of the molecular mechanisms governing memory decline with aging is still in its infancy. Recently, it has become apparent that most of the human genome is transcribed into non-coding RNAs (ncRNAs) rather than protein-coding mRNAs. Multiple types of ncRNAs are enriched in the central nervous system, and this large group of molecules may regulate the molecular complexity of the brain, its neurons, and synapses. Here, we review the current knowledge on the role of ncRNAs in synaptic plasticity, learning, and memory in the broader context of the aging brain and associated memory loss. We also discuss future directions to study the role of ncRNAs in the aging process.
    Ageing research reviews 09/2014; 17. DOI:10.1016/j.arr.2014.03.004 · 4.94 Impact Factor
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