title: Increased cortical synaptic activation of TrkB and downstream signaling markers in a mouse model of Down Syndrome.
abstract: Down Syndrome (DS), trisomy 21, is characterized by synaptic abnormalities and cognitive deficits throughout the lifespan and with development of Alzheimer's disease (AD) neuropathology and progressive cognitive decline in adults. Synaptic abnormalities are also present in the Ts65Dn mouse model of DS, but which synapses are affected and the mechanisms underlying synaptic dysfunction are unknown. Here we show marked increases in the levels and activation status of TrkB and associated signaling proteins in cortical synapses in Ts65Dn mice. Proteomic analysis at the single synapse level of resolution using array tomography (AT) uncovered increased colocalization of activated TrkB with signaling endosome related proteins, and demonstrated increased TrkB signaling. The extent of increases in TrkB signaling differed in each of the cortical layers examined and with respect to the type of synapse, with the most marked increases seen in inhibitory synapses. These findings are evidence of markedly abnormal TrkB-mediated signaling in synapses. They raise the possibility that dysregulated TrkB signaling contributes to synaptic dysfunction and cognitive deficits in DS.
authors.affiliation: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Molecular and Cellular Physiology, Stanford University, 279 Campus Drive, Stanford, CA 94305, USA. Electronic address: rnosheny@gmail.com.
authors.forename: R L
authors.initials: RL
authors.lastname: Nosheny
authors.affiliation: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: P V
authors.initials: PV
authors.lastname: Belichenko
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, 279 Campus Drive, Stanford, CA 94305, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Busse
authors.affiliation: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Weissmiller
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford Medical School, VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA.
authors.forename: V
authors.initials: V
authors.lastname: Dang
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford Medical School, VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA.
authors.forename: D
authors.initials: D
authors.lastname: Das
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford Medical School, VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA.
authors.forename: A
authors.initials: A
authors.lastname: Fahimi
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford Medical School, VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA.
authors.forename: A
authors.initials: A
authors.lastname: Salehi
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, 279 Campus Drive, Stanford, CA 94305, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Smith
authors.affiliation: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Mobley
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; D020813:Receptor, trkB
keywords: BDNF; Cerebral cortex; Down Syndrome; Signaling endosomes; Synapses; TrkB; Ts65Dn mice