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Gomes, André Raeli; Correia, Susana; Carvalho, Ana Luı́sa; Duarte, Carlos B.

doi:10.1023/a:1025610122776

Cited by 43 publications

(10 citation statements)

References 124 publications

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“…This contrasts with the role of NMDA receptors in synaptic delivery of GluR1-containing AMPA receptors following tetanic stimulation (39). The synaptic delivery of GluR1 induced by BDNF was sensitive to the Trk inhibitor K252a and was associated with the phosphorylation of the protein in Ser-831, the CaMKII and PKC phosphorylation site (24). Interestingly, GluR1 phosphorylation in Ser-831 was also observed upon induction of LTP in naïve synapses (34).…”

Section: Discussionmentioning

confidence: 96%

“…GluR1 is phosphorylated on Ser-831 during LTP, although this phosphorylation is not sufficient to induce synaptic delivery of AMPA receptors (24,26,33,34). Stimulation of cultured hippocampal neurons (7 DIV) with BDNF (100 ng/ml) increased the phosphorylation of GluR1 on Ser-831, as determined by Western blot using a phosphospecific antibody (Fig.…”

Section: Effect Of Bdnf On the Total Protein Levels Of Ampa Receptormentioning

confidence: 89%

“…1A). To better understand which signaling pathways may be involved in GluR1 phosphorylation following Trk receptor activation, and because Ser-831 is a phosphorylation site for protein kinase C (PKC) and Ca 2ϩ -calmodulin-dependent protein kinase II (CaMKII) (24,26), the effect of the kinase inhibitors chelerythrine (5 M) and KN-93 (10 M) was tested. Inhibition of PKC and CaMKII with chelerythrine and KN-93, respectively, inhibited GluR1 phosphorylation on Ser-831, suggesting that both pathways contribute to the effect of BDNF (Fig.…”

Section: Effect Of Bdnf On the Total Protein Levels Of Ampa Receptormentioning

confidence: 99%

“…The number, composition, and location of ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in neurons, together with receptor phosphorylation, are critically important factors in determining the neuronal response to glutamate, and play an important role in the mechanisms of synaptic plasticity (24). AMPA receptors are formed by the association of GluR1-GluR4 subunits, and their delivery to the synapse is tightly controlled by the intracellular signaling activity.…”

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confidence: 99%

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Brain-derived Neurotrophic Factor Regulates the Expression and Synaptic Delivery ofα-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor Subunits in Hippocampal Neurons

Caldeira

Melo

Pereira

et al. 2007

Journal of Biological Chemistry

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226

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Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity in the hippocampus, but the mechanisms involved are not fully understood. The neurotrophin couples synaptic activation to changes in gene expression underlying long term potentiation and short term plasticity. Here we show that BDNF acutely up-regulates GluR1, GluR2, and GluR3 ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits in 7-day tropomyosin-related kinase in vitro cultured hippocampal neurons. The increase in GluR1 and GluR2 protein levels in developing cultures was impaired by K252a, a Trk inhibitor, and by translation (emetine and anisomycin) and transcription (␣-amanitine and actinomycin D) inhibitors. Accordingly, BDNF increased the mRNA levels for GluR1 and GluR2 subunits. Biotinylation studies showed that stimulation with BDNF for 30 min selectively increased the amount of GluR1 associated with the plasma membrane, and this effect was abrogated by emetine. Under the same conditions, BDNF induced GluR1 phosphorylation on Ser-831 through activation of protein kinase C and Ca 2؉ -calmodulin-dependent protein kinase II. Chelation of endogenous extracellular BDNF with TrkB-IgG selectively decreased GluR1 protein levels in 14-day in vitro cultures of hippocampal neurons. Moreover, BDNF promoted synaptic delivery of homomeric GluR1 AMPA receptors in cultured organotypic slices, by a mechanism independent of NMDA receptor activation. Taken together, the results indicate that BDNF up-regulates the protein levels of AMPA receptor subunits in hippocampal neurons and induces the delivery of AMPA receptors to the synapse.Neurotrophins are essential for the development of the vertebrate nervous system, modulate synaptic function, and play an important role in synaptic plasticity (1, 2). Brain-derived neurotrophic factor (BDNF) 3 has been implicated in activitydependent synaptic plasticity, particularly in long term potentiation (LTP) induced by high frequency stimulation. Accordingly, LTP is impaired in the hippocampal CA1 region of animals deficient in BDNF, but it can be rescued by supplying the neurotrophin (3-5). Chelation of endogenous BDNF also prevents the induction of LTP by theta burst stimulation and reduces late phase LTP induced by high frequency stimulation (6, 7). Furthermore, the late phase LTP induced by tetanic stimulation was not observed in slices from BDNF knock-out mice and was also abrogated when TrkB receptors were blocked (8). Taken together, the available evidences point to a direct role of BDNF in the early and late phases of LTP.Binding of BDNF to TrkB receptors is followed by activation of intracellular signaling pathways, including the Ras/extracellular signal-regulated protein kinase, phospholipase C␥ (PLC␥), phosphatidylinositol-3-kinase/Akt, and Src pathways (9 -11). TrkB receptors are located on axon terminals and in the post-synaptic density of glutamatergic synapses (12-14), but whether the effects of BDNF on synaptic plasticity are mediated by pre-and/or post-sy...

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Section: Discussionmentioning

confidence: 96%

Section: Effect Of Bdnf On the Total Protein Levels Of Ampa Receptormentioning

confidence: 89%

Section: Effect Of Bdnf On the Total Protein Levels Of Ampa Receptormentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Brain-derived Neurotrophic Factor Regulates the Expression and Synaptic Delivery ofα-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor Subunits in Hippocampal Neurons

Caldeira

Melo

Pereira

et al. 2007

Journal of Biological Chemistry

Self Cite

226

212

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“…This increased calcium serves to initiate a cascade of events that includes: i) the activation of a variety of enzymes (kinases), some of which phosphorylate membrane proteins (e.g., sodium and calcium channels and the NMDA and AMPA receptors) to enhance depolarization [134][135][136], and ii) mitogen-activated protein kinases (MAP kinases) that initiate intracellular signaling leading to the activation of a variety of enzymes, such as PLA2, and in addition alter transcription, thus, increasing the expression of a variety of proteins and peptides (e.g., cyclooxygenase 2 and dynorphin) [40,49]. This downstream action is believed to herald long-term and persistent changes in function.…”

Section: Nmda-r /Ampa-rmentioning

confidence: 99%

Mechanisms of Neuropathic Pain

Yaksh¹,

Sorkin²

2005

CMCCNSA

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Injury to the peripheral nerve can lead to paradoxical changes in functioning such that there is an ongoing dysesthesia and an altered processing such that low threshold stimuli are responded to in humans and animals as if they were painful. What are the mechanisms underlying these anomalous behaviors? The biological changes induced by nerve injury are complex. To attribute functional relevance to the many changes, systematic preclinical work using well-defined behavioral models of nerve injury has been undertaken. Such studies have provided support for the important role in nerve injury-evoked pain behavior for a number of channels and receptors in the injured nerve, the dorsal root ganglion of the injured nerve, and the dorsal horn. These changes and their effect upon behavior are the subject of this review.

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A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity‐dependent synaptic and microglial transcriptomic changes in a late‐stage Alzheimer's mouse model

Latif‐Hernandez,

Yang,

Butler

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONTropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, and synaptic dysfunction.METHODSPTX‐BD10‐2 (BD10‐2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APPL/S) and wild‐type controls. Effects on memory and hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing.RESULTSIn APPL/S mice, BD10‐2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium‐calmodulin–dependent kinase II (CaMKII), and AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10‐2 also had potentially favorable effects on LTP‐dependent complement pathway and synaptic gene transcription.DISCUSSIONBD10‐2 prevented APPL/S/Aβ‐associated memory and LTP deficits, reduced abnormalities in synapse‐related signaling and activity‐dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.Highlights Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long‐term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model. Modulation of TrkB and TrkC regulates synaptic activity‐dependent transcription. TrkB and TrkC receptors are candidate targets for translational therapeutics. Electrophysiology combined with transcriptomics elucidates synaptic restoration. LTP identifies neuron and microglia AD‐relevant human‐mouse co‐expression modules.

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Untitled

Cited by 43 publications

References 124 publications

Brain-derived Neurotrophic Factor Regulates the Expression and Synaptic Delivery ofα-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor Subunits in Hippocampal Neurons

Brain-derived Neurotrophic Factor Regulates the Expression and Synaptic Delivery ofα-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor Subunits in Hippocampal Neurons

Mechanisms of Neuropathic Pain

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity‐dependent synaptic and microglial transcriptomic changes in a late‐stage Alzheimer's mouse model

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