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.
Publication types
-
Comparative Study
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Animals, Newborn
-
Biotinylation / methods
-
Blotting, Western / methods
-
Cytoskeletal Proteins / genetics
-
Cytoskeletal Proteins / physiology*
-
Electric Stimulation / methods
-
Enzyme Inhibitors / pharmacology
-
Excitatory Amino Acid Agonists / pharmacology
-
Gene Expression / physiology*
-
Green Fluorescent Proteins / metabolism
-
Hippocampus / cytology
-
In Vitro Techniques
-
Long-Term Synaptic Depression / drug effects
-
Long-Term Synaptic Depression / physiology
-
Long-Term Synaptic Depression / radiation effects
-
Models, Biological
-
Mutagenesis / physiology
-
N-Methylaspartate / pharmacology
-
Nerve Tissue Proteins / genetics
-
Nerve Tissue Proteins / physiology*
-
Neurons / drug effects
-
Neurons / physiology
-
Neurons / radiation effects
-
Okadaic Acid / pharmacology
-
Patch-Clamp Techniques / methods
-
RNA Interference / physiology
-
Rats
-
Receptors, AMPA / physiology*
-
Statistics, Nonparametric
-
Synaptic Transmission / physiology*
-
Time Factors
-
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
-
Cytoskeletal Proteins
-
Enzyme Inhibitors
-
Excitatory Amino Acid Agonists
-
Nerve Tissue Proteins
-
Receptors, AMPA
-
activity regulated cytoskeletal-associated protein
-
Green Fluorescent Proteins
-
Okadaic Acid
-
N-Methylaspartate
-
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid