Long-term potentiation and depression (LTP and LTD) are promising and widely studied examples of vertebrate synaptic plasticity. In LTP and LTD there is a persistent synaptic enhancement or decrement, respectively, seen following brief conditioning periods of synaptic activity. In both these forms of plasticity, which are leading models of memory, the trafficking of AMPA receptors (-Rs) at synapses plays a key role. The general aim of this grant has been to examine the subcellular signaling controlling AMPA-R trafficking. Recently, we have found that beta amyloid (A?), a peptide strongly implicated as a causative agent in Alzheimer's disease, has pronounced effects on AMPA-R trafficking. In this grant period, we will examine how A? can control the trafficking of synaptic AMPA receptors. Our recent studies show that A? recruits signaling used in LTD to remove synaptic AMPA receptors. Furthermore, loss of synaptic AMPA receptors leads to loss of dendritic spines and NMDA receptors;that is, loss of the synapse. Here we will determine the mechanisms by which A? leads to these events. Several complementing methodologies will be used, including molecular biology, electrophysiology, two-photon laser scanning microscopy, and electron microscopy. These studies will use organotypic rat hippocampal slices, dissociated cultured neurons and transgenic mice. The results of these studies will elucidate the mechanisms underlying Alzheimer's disease as well as provide potentially efficacious treatment strategies.
The specific aims are to determine: SA1: If A? allosterically up-modulates NMDA-R function;SA2: How A? interacts with synaptic plasticity;SA3: How A? leads to removal of synaptic AMPA-Rs;SA4: How A? leads to loss of synapses. There is growing evidence that one of the first targets of dysfunction in Alzheimer's disease is the synapse. We will examine the mechanisms by which beta amyloid, a molecule strongly implicated in the etiology of the disease, leads to synaptic dysfunction. By elucidating these mechanisms we will identify potentially therapeutic targets in the treatment of Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG032132-18
Application #
8234968
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Petanceska, Suzana
Project Start
1995-04-01
Project End
2013-06-30
Budget Start
2012-03-15
Budget End
2013-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$519,910
Indirect Cost
$183,398
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Alfonso, Stephanie I; Callender, Julia A; Hooli, Basavaraj et al. (2016) Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease. Sci Signal 9:ra47
Malinow, Roberto (2016) Depression: Ketamine steps out of the darkness. Nature 533:477-8
Reinders, Niels R; Pao, Yvonne; Renner, Maria C et al. (2016) Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3. Proc Natl Acad Sci U S A 113:E6526-E6534
Aow, Jonathan; Dore, Kim; Malinow, Roberto (2015) Conformational signaling required for synaptic plasticity by the NMDA receptor complex. Proc Natl Acad Sci U S A 112:14711-6
Dore, Kim; Aow, Jonathan; Malinow, Roberto (2015) Agonist binding to the NMDA receptor drives movement of its cytoplasmic domain without ion flow. Proc Natl Acad Sci U S A 112:14705-10
Tsai, Li-Chun Lisa; Xie, Lei; Dore, Kim et al. (2015) Zeta Inhibitory Peptide Disrupts Electrostatic Interactions That Maintain Atypical Protein Kinase C in Its Active Conformation on the Scaffold p62. J Biol Chem 290:21845-56
Alfonso, Stephanie; Kessels, Helmut W; Banos, Charles C et al. (2014) Synapto-depressive effects of amyloid beta require PICK1. Eur J Neurosci 39:1225-33
Nabavi, Sadegh; Fox, Rocky; Alfonso, Stephanie et al. (2014) GluA1 trafficking and metabotropic NMDA: addressing results from other laboratories inconsistent with ours. Philos Trans R Soc Lond B Biol Sci 369:20130145
Viger, Mathieu L; Sheng, Wangzhong; Doré, Kim et al. (2014) Near-infrared-induced heating of confined water in polymeric particles for efficient payload release. ACS Nano 8:4815-26
Nabavi, Sadegh; Fox, Rocky; Proulx, Christophe D et al. (2014) Engineering a memory with LTD and LTP. Nature 511:348-52

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