Increased Expression of the Immediate-Early Gene Arc/Arg3.1 Reduces AMPA Receptor-Mediated Synaptic Transmission

Emiliano M. Rial Verde; Jane Lee-Osbourne; Paul F F. Worley; Roberto Malinow; Hollis T T. Cline

doi:10.1016/j.neuron.2006.09.031

Increased Expression of the Immediate-Early Gene Arc/Arg3.1 Reduces AMPA Receptor-Mediated Synaptic Transmission

Emiliano M. Rial Verde, Jane Lee-Osbourne, Paul F F. Worley, Roberto Malinow, Hollis T T. Cline

School of Medicine

Research output: Contribution to journal › Article › peer-review

301 Scopus citations

Abstract

Arc/Arg3.1 is an immediate-early gene whose expression levels are increased by strong synaptic activation, including synapse-strengthening activity patterns. Arc/Arg3.1 mRNA is transported to activated dendritic regions, conferring the distribution of Arc/Arg3.1 protein both temporal correlation with the inducing stimulus and spatial specificity. Here, we investigate the effect of increased Arc/Arg3.1 levels on synaptic transmission. Surprisingly, Arc/Arg3.1 reduces the amplitude of synaptic currents mediated by AMPA-type glutamate receptors (AMPARs). This effect is prevented by RNAi knockdown of Arc/Arg3.1, by deleting a region of Arc/Arg3.1 known to interact with endophilin 3 or by blocking clathrin-coated endocytosis of AMPARs. In the hippocampal slice, Arc/Arg3.1 results in removal of AMPARs composed of GluR2 and GluR3 subunits (GluR2/3). Finally, Arc/Arg3.1 expression occludes NMDAR-dependent long-term depression. Our results demonstrate that Arc/Arg3.1 reduces the number of GluR2/3 receptors leading to a decrease in AMPAR-mediated synaptic currents, consistent with a role in the homeostatic regulation of synaptic strength.

Original language	English (US)
Pages (from-to)	461-474
Number of pages	14
Journal	Neuron
Volume	52
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2006.09.031
State	Published - Nov 9 2006

Keywords

MOLNEURO
SIGNALING

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2006.09.031

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@article{f539b72eed274f5592dfd68f0a502361,

title = "Increased Expression of the Immediate-Early Gene Arc/Arg3.1 Reduces AMPA Receptor-Mediated Synaptic Transmission",

abstract = "Arc/Arg3.1 is an immediate-early gene whose expression levels are increased by strong synaptic activation, including synapse-strengthening activity patterns. Arc/Arg3.1 mRNA is transported to activated dendritic regions, conferring the distribution of Arc/Arg3.1 protein both temporal correlation with the inducing stimulus and spatial specificity. Here, we investigate the effect of increased Arc/Arg3.1 levels on synaptic transmission. Surprisingly, Arc/Arg3.1 reduces the amplitude of synaptic currents mediated by AMPA-type glutamate receptors (AMPARs). This effect is prevented by RNAi knockdown of Arc/Arg3.1, by deleting a region of Arc/Arg3.1 known to interact with endophilin 3 or by blocking clathrin-coated endocytosis of AMPARs. In the hippocampal slice, Arc/Arg3.1 results in removal of AMPARs composed of GluR2 and GluR3 subunits (GluR2/3). Finally, Arc/Arg3.1 expression occludes NMDAR-dependent long-term depression. Our results demonstrate that Arc/Arg3.1 reduces the number of GluR2/3 receptors leading to a decrease in AMPAR-mediated synaptic currents, consistent with a role in the homeostatic regulation of synaptic strength.",

keywords = "MOLNEURO, SIGNALING",

author = "{Rial Verde}, {Emiliano M.} and Jane Lee-Osbourne and Worley, {Paul F F.} and Roberto Malinow and Cline, {Hollis T T.}",

note = "Funding Information: We thank A. Chowdhury (P. Worley Lab.) for pEGFPC3-Arc/Arg3.1, pBSK-Arc/Arg3.1, pBS-Arc/Arg3.1(Δ91–100), and Arc/Arg3.1 antibody, M. Sheng for pepΔA849-Q853, L. Manganas (G. Enikolopov Lab.) for β-tubulin antibody, and Fujisawa Healthcare for FK506. We also thank members of the Cline lab for their comments on the manuscript. This work was supported by Howard Hughes Medical Institute Predoctoral Fellowship, David and Fanny Luke Fellowship (E.M.R.V.), and National Institutes of Health (R.M. and H.T.C.). ",

year = "2006",

month = nov,

day = "9",

doi = "10.1016/j.neuron.2006.09.031",

language = "English (US)",

volume = "52",

pages = "461--474",

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T1 - Increased Expression of the Immediate-Early Gene Arc/Arg3.1 Reduces AMPA Receptor-Mediated Synaptic Transmission

AU - Rial Verde, Emiliano M.

AU - Lee-Osbourne, Jane

AU - Worley, Paul F F.

AU - Malinow, Roberto

AU - Cline, Hollis T T.

N1 - Funding Information: We thank A. Chowdhury (P. Worley Lab.) for pEGFPC3-Arc/Arg3.1, pBSK-Arc/Arg3.1, pBS-Arc/Arg3.1(Δ91–100), and Arc/Arg3.1 antibody, M. Sheng for pepΔA849-Q853, L. Manganas (G. Enikolopov Lab.) for β-tubulin antibody, and Fujisawa Healthcare for FK506. We also thank members of the Cline lab for their comments on the manuscript. This work was supported by Howard Hughes Medical Institute Predoctoral Fellowship, David and Fanny Luke Fellowship (E.M.R.V.), and National Institutes of Health (R.M. and H.T.C.).

PY - 2006/11/9

Y1 - 2006/11/9

N2 - Arc/Arg3.1 is an immediate-early gene whose expression levels are increased by strong synaptic activation, including synapse-strengthening activity patterns. Arc/Arg3.1 mRNA is transported to activated dendritic regions, conferring the distribution of Arc/Arg3.1 protein both temporal correlation with the inducing stimulus and spatial specificity. Here, we investigate the effect of increased Arc/Arg3.1 levels on synaptic transmission. Surprisingly, Arc/Arg3.1 reduces the amplitude of synaptic currents mediated by AMPA-type glutamate receptors (AMPARs). This effect is prevented by RNAi knockdown of Arc/Arg3.1, by deleting a region of Arc/Arg3.1 known to interact with endophilin 3 or by blocking clathrin-coated endocytosis of AMPARs. In the hippocampal slice, Arc/Arg3.1 results in removal of AMPARs composed of GluR2 and GluR3 subunits (GluR2/3). Finally, Arc/Arg3.1 expression occludes NMDAR-dependent long-term depression. Our results demonstrate that Arc/Arg3.1 reduces the number of GluR2/3 receptors leading to a decrease in AMPAR-mediated synaptic currents, consistent with a role in the homeostatic regulation of synaptic strength.

AB - Arc/Arg3.1 is an immediate-early gene whose expression levels are increased by strong synaptic activation, including synapse-strengthening activity patterns. Arc/Arg3.1 mRNA is transported to activated dendritic regions, conferring the distribution of Arc/Arg3.1 protein both temporal correlation with the inducing stimulus and spatial specificity. Here, we investigate the effect of increased Arc/Arg3.1 levels on synaptic transmission. Surprisingly, Arc/Arg3.1 reduces the amplitude of synaptic currents mediated by AMPA-type glutamate receptors (AMPARs). This effect is prevented by RNAi knockdown of Arc/Arg3.1, by deleting a region of Arc/Arg3.1 known to interact with endophilin 3 or by blocking clathrin-coated endocytosis of AMPARs. In the hippocampal slice, Arc/Arg3.1 results in removal of AMPARs composed of GluR2 and GluR3 subunits (GluR2/3). Finally, Arc/Arg3.1 expression occludes NMDAR-dependent long-term depression. Our results demonstrate that Arc/Arg3.1 reduces the number of GluR2/3 receptors leading to a decrease in AMPAR-mediated synaptic currents, consistent with a role in the homeostatic regulation of synaptic strength.

KW - MOLNEURO

KW - SIGNALING

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DO - 10.1016/j.neuron.2006.09.031

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SN - 0896-6273

VL - 52

SP - 461

EP - 474

JO - Neuron

JF - Neuron

IS - 3

ER -

Increased Expression of the Immediate-Early Gene Arc/Arg3.1 Reduces AMPA Receptor-Mediated Synaptic Transmission

Abstract

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