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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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
Li, Bo; Piriz, Joaquin; Mirrione, Martine et al. (2011) Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470:535-9
Makino, Hiroshi; Malinow, Roberto (2009) AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64:381-90
Kessels, Helmut W; Malinow, Roberto (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61:340-50
Li, Bo; Devidze, Nino; Barengolts, Denis et al. (2009) NMDA receptor phosphorylation at a site affected in schizophrenia controls synaptic and behavioral plasticity. J Neurosci 29:11965-72
Li, Bo; Woo, Ran-Sook; Mei, Lin et al. (2007) The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron 54:583-97