A promising and widely studied example of vertebrate synaptic plasticity is long-term potentiation (LTP), the persistent synaptic enhancement seen following a brief period of coincident pre- and postsynaptic activity. The cellular and molecular mechanisms responsible for LTP will likely elucidate physiological and pathological phenomena including learning, memory, developmental synapse specificity, neuronal death, and dementia. The cellular signaling responsible for generating LTP has been studied extensively. There is now compelling evidence that there is delivery of AMPA-type glutamate receptors to synapses during LTP. Here we will examine the cellular and molecular mechanisms of AMPA receptor delivery to synapses. We will characterize constitutive and regulated synaptic delivery. A specific model is proposed and tested. A regulated pathway effects transient delivery of receptors. The increased levels of receptors at synapses are maintained by constitutive one-for-one exchange between intracellular and synaptic pools. These issues will be examined with several complementing methodologies including electrophysiology, two-photon imaging of GFP-tagged receptors, molecular biology and transgenic technology. These studies will use rodent hippocampal slices (acute and organotypic). In this grant period we plan to: 1. measure delivery of recombinant AMPA receptors to synapses 2. determine which AMPA receptor subunits and domains control constitutive and regulated synaptic delivery 3. generate transgenic mice with dominant negative AMPA-receptor mutations that perturb regulated or constitutive delivery

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37MH049159-11
Application #
6392013
Study Section
Special Emphasis Panel (ZRG1-IFCN-7 (01))
Program Officer
Asanuma, Chiiko
Project Start
1992-05-01
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
11
Fiscal Year
2001
Total Cost
$518,529
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
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
Nabavi, Sadegh; Fox, Rocky; Proulx, Christophe D et al. (2014) Engineering a memory with LTD and LTP. Nature 511:348-52
Wu-Zhang, Alyssa X; Schramm, Cicely L; Nabavi, Sadegh et al. (2012) Cellular pharmacology of protein kinase M? (PKM?) contrasts with its in vitro profile: implications for PKM? as a mediator of memory. J Biol Chem 287:12879-85
Miyazaki, Tomoyuki; Takase, Kenkichi; Nakajima, Waki et al. (2012) Disrupted cortical function underlies behavior dysfunction due to social isolation. J Clin Invest 122:2690-701
Malinow, Roberto (2012) New developments on the role of NMDA receptors in Alzheimer's disease. Curr Opin Neurobiol 22:559-63
Makino, Hiroshi; Malinow, Roberto (2011) Compartmentalized versus global synaptic plasticity on dendrites controlled by experience. Neuron 72:1001-11
Wei, Wei; Nguyen, Louis N; Kessels, Helmut W et al. (2010) Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci 13:190-6
Malinow, Roberto; Hayashi, Yasunori; Maletic-Savatic, Mirjana et al. (2010) Introduction of green fluorescent protein (GFP) into hippocampal neurons through viral infection. Cold Spring Harb Protoc 2010:pdb.prot5406
Kessels, Helmut W; Nguyen, Louis N; Nabavi, Sadegh et al. (2010) The prion protein as a receptor for amyloid-beta. Nature 466:E3-4; discussion E4-5
Makino, Hiroshi; Malinow, Roberto (2009) AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64:381-90

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