Novel roles by glutamatergic receptors in the synaptic effects of beta amyloid Long-term potentiation and depression (LTP and LTD) are promising and widely studied examples of vertebrate synaptic plasticity in which 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, NMDA receptors (-Rs) and AMPA receptors (-Rs) at synapses play key and distinct roles. The general aim of this grant has been to examine the subcellular signaling controlling LTP and LTD. 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 requiring a novel form of NMDA-R signaling. In this grant period, we will examine the different roles played by NMDA-Rs and AMPA-Rs and their associated proteins in the effects of A? on synapses. Our preliminary studies show that a non-ionic form of NMDA-R signaling as well as a specific subunit of AMPA-Rs are required for A? to modify excitatory synapses. Here we will examine these findings using several complementing methodologies including molecular biology, electrophysiology, and two-photon laser scanning microscopy. These studies will use heterologous cell lines, organotypic rat hippocampal slices and genetically modified 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:
Specific Aim 1 : The role played by NMDA-Rs and associated molecules in A?-induced synaptic depression Specific Aim 2: The role played by AMPA-Rs and associated molecules in A?-induced synaptic depression

Public Health Relevance

Synapses, the sites of communication between nerve cells, are thought to be early targets of damage in Alzheimer's disease. Abnormally high levels of the peptide A? is thought to be causative in the disease. Understanding such a process may provide insight into treatment of Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Dore, Kim; Stein, Ivar S; Brock, Jennifer A et al. (2017) Unconventional NMDA Receptor Signaling. J Neurosci 37:10800-10807
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
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
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
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; Proulx, Christophe D et al. (2014) Engineering a memory with LTD and LTP. Nature 511:348-52

Showing the most recent 10 out of 27 publications