Increased cortical synaptic activation of TrkB and downstream signaling markers in a mouse model of Down Syndrome

R.L. Nosheny; P.V. Belichenko; B.L. Busse; A.M. Weissmiller; V. Dang; D. Das; A. Fahimi; A. Salehi; S.J. Smith; W.C. Mobley

Neurobiology of Disease (May 2015)

Increased cortical synaptic activation of TrkB and downstream signaling markers in a mouse model of Down Syndrome

R.L. Nosheny,
P.V. Belichenko,
B.L. Busse,
A.M. Weissmiller,
V. Dang,
D. Das,
A. Fahimi,
A. Salehi,
S.J. Smith,
W.C. Mobley

Affiliations

R.L. Nosheny: 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; Corresponding author at: Center for Imaging of Neurodegenerative Diseases, 4150 Clement Street, San Francisco, CA 94121, USA. Fax: +1 415 668 2864.
P.V. Belichenko: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
B.L. Busse: Department of Molecular and Cellular Physiology, Stanford University, 279 Campus Drive, Stanford, CA 94305, USA
A.M. Weissmiller: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
V. Dang: Department of Psychiatry & Behavioral Sciences, Stanford Medical School, VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA
D. Das: Department of Psychiatry & Behavioral Sciences, Stanford Medical School, VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA
A. Fahimi: Department of Psychiatry & Behavioral Sciences, Stanford Medical School, VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA
A. Salehi: Department of Psychiatry & Behavioral Sciences, Stanford Medical School, VA Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304, USA
S.J. Smith: Department of Molecular and Cellular Physiology, Stanford University, 279 Campus Drive, Stanford, CA 94305, USA
W.C. Mobley: Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

Journal volume & issue: Vol. 77
pp. 173 – 190

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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