Connecting Activity to Endocytosis
Authors: Gough Nancy R. 
Published: December 2006

Four articles in
Neuron
provide insight into the function of Arc (also known as Arg3.1, Arc/Arg3.1), which has long been known as a marker for synaptic activity, after which Arc/Arg3.1 mRNA is synthesized and transported to active synapses or is redistributed from inactive to active synapses. These results, along with a review of the Arc/Arg3.1 literature, are discussed by Tzingounis and Nicoll. Using knockout mice, Plath
et al
. found that loss of Arc/Arg3.1 disrupted long-term memory formation (spatial learning, fear conditioning, conditioned taste aversion, and object recognition), without impairing short-term memory. Analysis of long-term potentiation (LTP) and long-term depression (LTD) in the knockout mice in vivo or in cultured cells showed that the initial phase of LTP was enhanced but the late phase of LTP was inhibited and that LTD was diminished at all times. Shepherd
et al
. investigated the role of Arc/Arg3.1 in another form of plasticity called homeostatic synaptic scaling. One example of this is the reciprocal changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in response to chronic synaptic activation or synaptic blockade: Numbers of AMPA receptors at the surface increase under conditions of chronic inhibition and decrease under conditions of chronic stimulation. Shepherd
et al
. found that Arc/Arg3.1 abundance in cultured cortical neurons was inversely correlated with the activity in the cultures: When activity was blocked with tetrodotoxin (TTX), Arc/Arg3.1 abundance decreased, and when activity was enhanced with bicuculline (Bic), Arc/Arg3.1 abundance was increased. Overexpression of Arc/Arg3.1 decreased the abundance of AMPA receptors at the surface and prevented TTX-induced increase in AMPA receptors, blocked the scaling effect, and reduced the amplitude of miniature excitatory postsynaptic currents (mEPSCs). In neurons from Arc/Arg3.1 knockout mice, synaptic scaling in response to either TTX or Bic was completely absent. Thus, from these two studies it appears that Arc/Arg3.1 plays an essential role in Hebbian forms of synaptic plasticity (LTP and LTD) and homeostatic synaptic plasticity and that the mechanism may be regulation of trafficking of AMPA receptors to or from the surface. Rial Verde
et al
. show that in organotypic hippocampal slices, the abundance of Arc/Arg3.1 correlates inversely with AMPA-mediated activity. Overexpression of Arc/Arg3.1 promoted the endocytosis of AMPA receptors. Chowdhury
et al
. show that Arc/Arg3.1 interacts with two components of the endocytosis machinery: endophilin and dynamin. The interaction with these proteins was required for overexpressed Arc/Arg3.1 to affect AMPA receptor endocytosis. Thus, Arc/Arg3.1 appears to connect synaptic activity to AMPA receptor endocytosis, which controls the abundance of AMPA receptors at the surface and the AMPA receptor-mediated activity of the synapse.

A. V. Tzingounis, R. A. Nicoll, Arc/Arg3.1: Linking gene expression to synaptic plasticity and memory.
Neuron
52
, 403-407 (2006).
[PubMed]

N. Plath, O. Ohana, B. Dammermann, M. L. Errington, D. Schmitz, C. Gross, X. Mao, A. Engelsberg, C. Mahlke, H. Welzl, U. Kobalz, A. Stawrakakis, E. Fernandez, R. Waltereit, A. Bick-Sander, E. Therstappen, S. F. Cooke, V. Blanquet, W. Wurst, B. Salmen, M. R. Bösl, H.-P. Lipp, S. G. N. Grant, T. V. P. Bliss, D. P. Wolfer, D. Kuhl, Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories.
Neuron
52
, 437-444 (2006).
[PubMed]

J. D. Shepherd, G. Rumbaugh, J. Wu, S. Chowdhury, N. Plath, D. Kuhl, R. L. Huganir, P. F. Worley, Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors.
Neuron
52
, 475-484 (2006).
[PubMed]

E. M. Rial Verde, J. Lee-Osbourne, P. F. Worley, R. Malinow, H. T. Cline, Increased expression of the immediate-early gene
Arc/Arg3.1
reduces AMPA receptor-mediated synaptic transmission.
Neuron
52
, 461-474 (2006).
[PubMed]

S. Chowdhury, J. D. Shepherd, H. Okuno, G. Lyford, R. S. Petralia, N. Plath, D. Kuhl, R. L. Huganir, P. F. Worley, Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking.
Neuron
52
, 445-459 (2006).
[PubMed]