Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission.
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.
Rial Verde
Emiliano M
EM
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Lee-Osbourne
Jane
J
Worley
Paul F
PF
Malinow
Roberto
R
Cline
Hollis T
HT
D000818:Animals; D000831:Animals, Newborn; D019921:Biotinylation / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008954:Models, Biological; D016296:Mutagenesis / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D019319:Okadaic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000502:physiology*; D018709:Statistics, Nonparametric; D009435:Synaptic Transmission / Q000502:physiology*; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C092069:activity regulated cytoskeletal-associated protein; D049452:Green Fluorescent Proteins; D019319:Okadaic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid