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An increase in basal BDNF provokes hyperactivation of the Akt-mammalian target of rapamycin pathway and deregulation of local dendritic translation in a mouse model of Down's syndrome.

As in other diseases associated with mental retardation, dendrite morphology and synaptic plasticity are impaired in Down's syndrome (DS). Both these features of neurons are critically influenced by BDNF, which regulates local dendritic translation through phosphatidylinositol 3-kinase-Akt-mammalian... Full description

Journal Title: The Journal of neuroscience : the official journal of the Society for Neuroscience June 29, 2011, Vol.31(26), pp.9445-9455
Main Author: Troca-Marín, José Antonio
Other Authors: Alves-Sampaio, Alexandra , Montesinos, María Luz
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1529-2401 ; DOI: 10.1523/JNEUROSCI.0011-11.2011
Link: http://search.proquest.com/docview/874484973/?pq-origsite=primo
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title: An increase in basal BDNF provokes hyperactivation of the Akt-mammalian target of rapamycin pathway and deregulation of local dendritic translation in a mouse model of Down's syndrome.
format: Article
creator:
  • Troca-Marín, José Antonio
  • Alves-Sampaio, Alexandra
  • Montesinos, María Luz
subjects:
  • Animals–Genetics
  • Brain-Derived Neurotrophic Factor–Metabolism
  • Cells, Cultured–Drug Effects
  • Dendrites–Genetics
  • Disease Models, Animal–Metabolism
  • Down Syndrome–Genetics
  • Hippocampus–Metabolism
  • Immunohistochemistry–Metabolism
  • Mice–Drug Effects
  • Mice, Transgenic–Metabolism
  • Neurons–Drug Effects
  • Phosphorylation–Physiology
  • Protein Biosynthesis–Drug Effects
  • Proto-Oncogene Proteins C-Akt–Physiology
  • Signal Transduction–Genetics
  • Sirolimus–Metabolism
  • Statistics, Nonparametric–Drug Effects
  • Tor Serine-Threonine Kinases–Physiology
  • Tor Serine-Threonine Kinases–Pharmacology
  • Tor Serine-Threonine Kinases–Metabolism
  • Brain-Derived Neurotrophic Factor
  • Tor Serine-Threonine Kinases
  • Proto-Oncogene Proteins C-Akt
  • Sirolimus
ispartof: The Journal of neuroscience : the official journal of the Society for Neuroscience, June 29, 2011, Vol.31(26), pp.9445-9455
description: As in other diseases associated with mental retardation, dendrite morphology and synaptic plasticity are impaired in Down's syndrome (DS). Both these features of neurons are critically influenced by BDNF, which regulates local dendritic translation through phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (mTOR) and Ras-ERK signaling cascades. Here we show that the levels of BDNF and phosphorylated Akt-mTOR (but not Ras-ERK) pathway proteins are augmented in hippocampal dendrites of Ts1Cje mice, a DS model. Consequently, the rate of local dendritic translation is abnormally high and the modulatory effect of exogenous BDNF is lost. Interestingly, rapamycin (a Food and Drug Administration-approved drug) restores normal levels of phosphorylated Akt-mTOR proteins and normal rates of local translation in Ts1Cje neurons, opening new therapeutic perspectives for DS. The NMDAR inhibitors APV, MK-801, and memantine also restore the normal levels of phospho-mTOR in dendrites of Ts1Cje hippocampal neurons. We propose a model to explain how BDNF-mediated regulation of local translation is lost in the Ts1Cje hippocampus through the establishment of a glutamatergic positive-feedback loop. Together, these findings help elucidate the mechanisms underlying altered synaptic plasticity in DS.
language: eng
source:
identifier: E-ISSN: 1529-2401 ; DOI: 10.1523/JNEUROSCI.0011-11.2011
fulltext: fulltext
issn:
  • 15292401
  • 1529-2401
url: Link


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titleAn increase in basal BDNF provokes hyperactivation of the Akt-mammalian target of rapamycin pathway and deregulation of local dendritic translation in a mouse model of Down's syndrome.
creatorTroca-Marín, José Antonio ; Alves-Sampaio, Alexandra ; Montesinos, María Luz
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ispartofThe Journal of neuroscience : the official journal of the Society for Neuroscience, June 29, 2011, Vol.31(26), pp.9445-9455
identifierE-ISSN: 1529-2401 ; DOI: 10.1523/JNEUROSCI.0011-11.2011
subjectAnimals–Genetics ; Brain-Derived Neurotrophic Factor–Metabolism ; Cells, Cultured–Drug Effects ; Dendrites–Genetics ; Disease Models, Animal–Metabolism ; Down Syndrome–Genetics ; Hippocampus–Metabolism ; Immunohistochemistry–Metabolism ; Mice–Drug Effects ; Mice, Transgenic–Metabolism ; Neurons–Drug Effects ; Phosphorylation–Physiology ; Protein Biosynthesis–Drug Effects ; Proto-Oncogene Proteins C-Akt–Physiology ; Signal Transduction–Genetics ; Sirolimus–Metabolism ; Statistics, Nonparametric–Drug Effects ; Tor Serine-Threonine Kinases–Physiology ; Tor Serine-Threonine Kinases–Pharmacology ; Tor Serine-Threonine Kinases–Metabolism ; Brain-Derived Neurotrophic Factor ; Tor Serine-Threonine Kinases ; Proto-Oncogene Proteins C-Akt ; Sirolimus
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descriptionAs in other diseases associated with mental retardation, dendrite morphology and synaptic plasticity are impaired in Down's syndrome (DS). Both these features of neurons are critically influenced by BDNF, which regulates local dendritic translation through phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (mTOR) and Ras-ERK signaling cascades. Here we show that the levels of BDNF and phosphorylated Akt-mTOR (but not Ras-ERK) pathway proteins are augmented in hippocampal dendrites of Ts1Cje mice, a DS model. Consequently, the rate of local dendritic translation is abnormally high and the modulatory effect of exogenous BDNF is lost. Interestingly, rapamycin (a Food and Drug Administration-approved drug) restores normal levels of phosphorylated Akt-mTOR proteins and normal rates of local translation in Ts1Cje neurons, opening new therapeutic perspectives for DS. The NMDAR inhibitors APV, MK-801, and memantine also restore the normal levels of phospho-mTOR in dendrites of Ts1Cje hippocampal neurons. We propose a model to explain how BDNF-mediated regulation of local translation is lost in the Ts1Cje hippocampus through the establishment of a glutamatergic positive-feedback loop. Together, these findings help elucidate the mechanisms underlying altered synaptic plasticity in DS.
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titleAn increase in basal BDNF provokes hyperactivation of the Akt-mammalian target of rapamycin pathway and deregulation of local dendritic translation in a mouse model of Down's syndrome.
authorTroca-Marín, José Antonio ; Alves-Sampaio, Alexandra ; Montesinos, María Luz
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