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.
abstract: 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.
authors.affiliation: Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Sevilla, E-41009, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Troca-Marín
authors.forename: Alexandra
authors.initials: A
authors.lastname: Alves-Sampaio
authors.forename: María Luz
authors.initials: ML
authors.lastname: Montesinos
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D014176:Protein Biosynthesis / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus