The rapid cycling of AMPA receptors (AMPARs) into and out of the membrane maintains neurotransmission at a number of CMS synapses. The cycling of AMPARs in the hippocampus and cortex is dynamically regulated by changes in levels of basal synaptic transmission and has been proposed to play a role in certain forms of synaptic plasticity. It remains unclear, however, whether the cycling of AMPARs also occurs at synapses not believed to exhibit postsynaptic forms of activity dependent plasticity. Additionally the question remains as to whether there are differences in the regulation of receptor trafficking at synapses that are subject to very different patterns of synaptic activation. For example, while many CMS synapses function primarily through intermittent, activity driven neurotransmitter release, synapses in the retina are subject to tonic glutamate release and stimulus dependent cessation of synaptic transmission. We are investigating the trafficking of AMPARs in retinal neurons and its regulation by activity. Our preliminary data demonstrates that, GluR2-c6ntaining AMPARs, can be rapidly cycled at the extrasynaptic membrane in the retina.;? Wpwever, contrary to in hippocampal synapses, activity in the retina stabilizes AMPARs in a non-cycling*?""""""""""""""""' mpde. This reversible process is modulated by physiological light stimuli. Experiments in this proposal,will jseek to test the hypothesis, that normal light/dark cycles drive changes in the cycling of GluR2 -containihg AMPARs thereby impacting functional signaling in the retina. Experiments in'Aim.l .will establish the physiological conditions that mediate changes in the cycling of AMPARs in the retina. In.
Aim 2 we will seek to.determine the molecular mechanisms by which activity links to changes in.the cycling of AMPARs. Finally, inAim 3 we will characterize the physiological significance of altered AMPAR cycling on the function of .. synaptic transmission in the retina. Results from these experiments will greatly enhance our understanding of.the function and regulation.of signaling in the retina potentially identifying the existence a previously . ?, unknown form activity dependent of retinal plasticity. This should provide valuable insight into possible therapeutic treatments relevant to diseases of retinal development and degeneration. : :

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY017428-03S1
Application #
7847118
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2007-03-01
Project End
2012-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
3
Fiscal Year
2009
Total Cost
$68,671
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Wang, Ai Ling; Carroll, Reed C; Nawy, Scott (2014) Down-regulation of the RNA editing enzyme ADAR2 contributes to RGC death in a mouse model of glaucoma. PLoS One 9:e91288
Jones, Rebecca S; Pedisich, Marina; Carroll, Reed C et al. (2014) Spatial organization of AMPAR subtypes in ON RGCs. J Neurosci 34:656-61
Casimiro, Tanya M; Nawy, Scott; Carroll, Reed C (2013) Molecular mechanisms underlying activity-dependent AMPA receptor cycling in retinal ganglion cells. Mol Cell Neurosci 56:384-92
Jones, Rebecca S; Carroll, Reed C; Nawy, Scott (2012) Light-induced plasticity of synaptic AMPA receptor composition in retinal ganglion cells. Neuron 75:467-78
Snellman, Josefin; Kaur, Tejinder; Shen, Yin et al. (2008) Regulation of ON bipolar cell activity. Prog Retin Eye Res 27:450-63
Xia, Yingqiu; Nawy, Scott; Carroll, Reed C (2007) Activity-dependent synaptic plasticity in retinal ganglion cells. J Neurosci 27:12221-9
Xia, Yingqiu; Carroll, Reed C; Nawy, Scott (2006) State-dependent AMPA receptor trafficking in the mammalian retina. J Neurosci 26:5028-36