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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Petanceska, Suzana
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Müller, Michaela Kerstin; Jacobi, Eric; Sakimura, Kenji et al. (2018) NMDA receptors mediate synaptic depression, but not spine loss in the dentate gyrus of adult amyloid Beta (A?) overexpressing mice. Acta Neuropathol Commun 6:110
Carrico, Zachary M; Le, Geneva; Malinow, Roberto (2017) A fluorescence assay for detecting amyloid-? using the cytomegalovirus enhancer/promoter. J Biol Methods 4:
Dore, Kim; Stein, Ivar S; Brock, Jennifer A et al. (2017) Unconventional NMDA Receptor Signaling. J Neurosci 37:10800-10807
Malinow, Roberto (2016) Depression: Ketamine steps out of the darkness. Nature 533:477-8
Dore, Kim; Aow, Jonathan; Malinow, Roberto (2016) The Emergence of NMDA Receptor Metabotropic Function: Insights from Imaging. Front Synaptic Neurosci 8:20
Alfonso, Stephanie I; Callender, Julia A; Hooli, Basavaraj et al. (2016) Gain-of-function mutations in protein kinase C? (PKC?) may promote synaptic defects in Alzheimer's disease. Sci Signal 9:ra47
Reinders, Niels R; Pao, Yvonne; Renner, Maria C et al. (2016) Amyloid-? 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
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

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