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
| 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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