During development, activity refines neural connections by modulating the number and relative strength of synaptic inputs onto neurons. Long-term depression (LTD) is a form of synaptic plasticity believed to play a critical role in neural circuit formation, perhaps as an initial step in synapse elimination. Multiple signaling pathways can trigger LTD in a single neuron, however, the relative functional impact of these different pathways on mediating synaptic input is unclear. Two forms of LTD have been identified in hippocampal CA1 pyramidal neurons, metabotropic glutamate receptor (mGluR) - and NMDA- type glutamate receptor (NMDAR)-mediated, which have been proposed to share regulated endocytosis of synaptic AMPA-type glutamate receptors as an expression mechanism. However, differences in downstream signaling pathways and the absence of functional interaction between synaptic depressions activated by these receptors imply that they trigger the internalization of AMPARs through distinct, as yet undefined, mechanisms. We have found that activation of the NMDAR- or mGluR- coupled signaling pathways in pyramidal neurons actually causes the internalization of different populations of AMPARs. Furthermore, our preliminary studies suggest that the colocalization of the AMPAR- interacting proteins receptors GRIP with receptors at a subset of surface sites likely plays a role in mediating this signaling pathway selective AMPAR endocytosis. In this proposal, we will test the hypothesis that NMDARs and mGluRs target AMPARs for internalization from completely distinct synaptic sites mediated by the localized expression of GRIP. Furthermore, we will test whether GRIP promotes selective AMPAR endocytosis by establishing a stabilized synaptic population of AMPARs specifically targeted for internalization by mGluR activation but resistant to the actions of NMDARs. Results from these studies should provide important insight into mechanisms of AMPAR trafficking. In addition they should provide novel evidence that two forms of depression can differentially shape the connectivity of developing neuronal circuitry by acting at distinct synaptic sites on a single neuron. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049661-02
Application #
6862734
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
2004-03-01
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$344,470
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Marsden, Kurt C; Shemesh, Adi; Bayer, K Ulrich et al. (2010) Selective translocation of Ca2+/calmodulin protein kinase IIalpha (CaMKIIalpha) to inhibitory synapses. Proc Natl Acad Sci U S A 107:20559-64
Xia, Yingqiu; Nawy, Scott; Carroll, Reed C (2007) Activity-dependent synaptic plasticity in retinal ganglion cells. J Neurosci 27:12221-9
Sossa, Kenneth G; Beattie, Jennifer B; Carroll, Reed C (2007) AMPAR exocytosis through NO modulation of PICK1. Neuropharmacology 53:92-100
Marsden, Kurt C; Beattie, Jennifer B; Friedenthal, Jenna et al. (2007) NMDA receptor activation potentiates inhibitory transmission through GABA receptor-associated protein-dependent exocytosis of GABA(A) receptors. J Neurosci 27:14326-37
Davidkova, Genoveva; Carroll, Reed C (2007) Characterization of the role of microtubule-associated protein 1B in metabotropic glutamate receptor-mediated endocytosis of AMPA receptors in hippocampus. J Neurosci 27:13273-8
Xia, Yingqiu; Carroll, Reed C; Nawy, Scott (2006) State-dependent AMPA receptor trafficking in the mammalian retina. J Neurosci 26:5028-36
Grooms, Sonja Y; Noh, Kyung-Min; Regis, Roodland et al. (2006) Activity bidirectionally regulates AMPA receptor mRNA abundance in dendrites of hippocampal neurons. J Neurosci 26:8339-51
Sossa, K G; Court, B L; Carroll, R C (2006) NMDA receptors mediate calcium-dependent, bidirectional changes in dendritic PICK1 clustering. Mol Cell Neurosci 31:574-85