Metabotropic glutamate receptor (mGluR)-dependent long-term depression (mGluR-LTD) relies on dendritic protein synthesis that occurs within minutes of mGluR activation, but the identities of the synthesized proteins are largely unknown. Two new studies show that the rapid translation of activity-regulated cytoskeleton-associated protein (ARC; also termed activity-regulated gene of 3.1 kb (ARG3.1)) is essential for mGluR-LTD. Both groups of researchers used hippocampal neuronal cultures and acute slices to investigate the molecular mechanism of mGluR-LTD.

Both studies initially established that induction of LTD with the mGluR agonist dihydroxyphenylglycine (DHPG) in hippocampal cultures led to a long-term decrease in surface AMPARs (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). This could be blocked by inhibiting mRNA translation. As Arc/Arg3.1 mRNA is present in dendrites, and as ARC/ARG3.1 is known to stimulate AMPAR endocytosis, both research groups measured dendritic ARC/ARG3.1 protein levels following the stimulation of neurons with DHPG. Both groups observed a significant increase in dendritic Arc/Arg3.1 protein levels. Blocking protein synthesis prevented this increase, whereas blocking DNA transcription did not, indicating that mGluR-LTD requires de novo protein synthesis.

Waung et al. obtained similar results with acute hippocampal slices in which the dendrites had been mechanically severed from the nerve cell body, suggesting that ARC/ARG3.1 is locally synthesized from pre-existing, dendritic mRNA. Furthermore, mGluR-LTD was impaired in slices from Arc/Arg3.1-knockout mice (Park, Park et al.) or when Arc/Arg3.1 mRNA translation was acutely prevented by antisense oligonucleotides (Waung et al.). The latter finding suggests that rapid translation of Arc/Arg3.1 mRNA is required for mGluR-LTD.

Paradoxically, Park, Park et al. revealed that low doses of the protein-synthesis inhibitor cycloheximide increased the levels of ARC/ARG3.1 protein. This pointed the authors towards eukaryotic translation elongation factor 2 (EEF2), as EEF2 that has been phosphorylated by EEF2 kinase (EEF2K) inhibits elongation in protein synthesis but has been shown to increase the translation of certain mRNAs. Co-immunoprecipitation studies showed that mGluRs directly associate with EEF2K, and that this interaction is reduced by mGluR activation.

Park, Park et al. investigated hippocampal slices from Eef2k-knockout mice, and showed that mGluR-LTD is absent in these slices and that de novo ARC/ARG3.1 synthesis is absent in Eefk2-knockout neurons. The authors concluded that the EEF2K–EEF2–ARC/ARG3.1 pathway is important for mGluR-LTD.

In a mouse model of Fragile X syndrome, in which the dendritic mRNA-binding protein fragile X mental retardation protein (FMRP) is mutated and in which Arc/Arg3.1 mRNA translation is de-repressed, mGluR-LTD is abnormal. In neuronal cultures from Fmr1-knockout mice, the increase in ARC/ARG3.1 protein levels after DHPG stimulation was absent. Similarly, in slices from Arc/Arg3.1;Fmr1 double-knockout mice, DHPG-evoked LTD was impaired. This again highlights the importance of the EEF2K–EEF2–ARG/ARG3.1 pathway in mGluR-LTD.

These results demonstrate that local, rapid translation of Arc/Arg3.1 mRNA is essential for mGluR-LTD but not for NMDAR (N-methyl-D-aspartate receptor)-dependent LTD, and give insight into the mechanistic differences between these two forms of LTD. mGluR-LTD might function to mediate adaptive behaviours, as rapid protein synthesis in dendrites probably contributes to synapse-selective, long-lasting forms of plasticity.